Visible-Light-Induced Palladium-Catalyzed Selective Defluoroarylation of Trifluoromethylarenes with Arylboronic Acids

Article abstract of DOI:10.1021/jacs.1c07459

Selective functionalization of inactive C(sp3)-F bonds to prepare medicinally interesting aryldifluoromethylated compounds remains challenging. One promising route is the transition-metal-catalyzed cross-coupling through oxidative addition of the C(sp3)-F bond in trifluoromethylarenes (ArCF3), which are ideal precursors for this process due to their ready availability and low cost. Here, we report an unprecedented excited-state palladium catalysis strategy for selective defluoroarylation of trifluoromethylarenes with arylboronic acids. This visible-light-induced palladium-catalyzed cross-coupling proceeds under mild reaction conditions and allows transformation of a variety of arylboronic acids and ArCF3. Preliminary mechanistic studies reveal that the oxidative addition of the C(sp3)-F bond in ArCF3 to excited-state palladium(0) via a single electron transfer pathway is responsible for the C(sp3)-F bond activation.

Full text of DOI:10.1021/jacs.1c07459

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Visible-Light-Induced Palladium-Catalyzed Selective
Defluoroarylation of Trifluoromethylarenes with Arylboronic Acids
Yun-Cheng Luo, Fei-Fei Tong, Yanxia Zhang, Chun-Yang He, and Xingang Zhang*
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ABSTRACT: Selective functionalization of inactive C(sp3)−F
bonds to prepare medicinally interesting aryldifluoromethylated
compounds remains challenging. One promising route is the
transition-metal-catalyzed cross-coupling through oxidative addition
of the C(sp3)−F bond in trifluoromethylarenes (ArCF3), which are
ideal precursors for this process due to their ready availability and
low cost. Here, we report an unprecedented excited-state palladium
catalysis strategy for selective defluoroarylation of trifluoromethylar-
enes with arylboronic acids. This visible-light-induced palladium-
catalyzed cross-coupling proceeds under mild reaction conditions
and allows transformation of a variety of arylboronic acids and
ArCF3. Preliminary mechanistic studies reveal that the oxidative
addition of the C(sp3)−F bond in ArCF3 to excited-state palladium(0) via a single electron transfer pathway is responsible for the
C(sp3)−F bond activation.
α,α-difluororobenzylic cations through strong Lewis acid-
promoted processes;7 (3) α,α-difluororobenzylic radicals
generated by single-electron reduction (e.g., using excited
photocatalysts).8 Besides the three well-established pathways,
we envisioned that the transition-metal-catalyzed cross-
coupling through oxidative addition of a C−F bond in
ArCF3 would open a new pathway in the selective
functionalization of the inactive C(sp3)−F bond. Such a
strategy would provide new mechanistic insight into the C−F
bond activation, and it would enable the direct synthesis of
medicinally interesting ArCF2−Ar structures (Figure 1D),9
which are difficult to achieve by the aforementioned methods
due to the over-defluorinations and lack of an efficient catalytic
system.
To realize this transition-metal-catalyzed strategy, two
crucial issues should be addressed: (1) the oxidative addition
of a transition metal to the C(sp3)−F bond in CF3, one of the
strongest single bonds to carbon (Figure 1C);4 (2) the
suppression of over-defluorination side reactions, which
probably follow the dissociation of the first C−F bond in
CF3 with a relatively faster reaction rate, because of the
decreasing bond dissociation energy (BDE) of the C−F bonds
INTRODUCTION
■
The prominent applications of organofluorinated compounds
in life and materials sciences have triggered substantial
endeavors in tailoring organic molecules with fluorine
atom(s).1 Over the past decade, impressive achievements
have been made in the field, most of which focus on the site-
selective fluorination and fluoroalkylation reactions.2 Recently,
the selective C−F bond functionalization to prepare
fluorinated compounds has received increasing attention,
because of its significance in both fundamental research and
applications in chemical synthesis and degradation of environ-
mentally persistent fluorinated molecules.3 As a consequence,
important progress in the selective functionalization of the
C(sp2)−F bond has been achieved (Figure 1A).3a,c However,
the reaction of the C(sp3)−F bond on an inactive skeleton,
such as trifluoromethylarenes (ArCF3), remains challenging
(Figure 1A).3d,e Especially, powerful transition-metal catalysis
has not yet been utilized in activating the inactive C−F bond in
CF3, because of difficulties in oxidative addition of robust
C(sp3)−F bonds in perfluoroalkyl groups (e.g., CF3).4,5 As
such, a new method to overcome this formidable challenge is
highly desirable.
ArCF3 are a series of ideal precursors to prepare medicinally
interesting difluoroalkylated arenes (ArCF2−FG),1 due to their
ready availability, low cost, and avoiding of multistep synthesis
of difluoroalkylating reagents. Generally, three different α,α-
difluororobenzylic intermediates can be generated in situ from
ArCF3 (Figure 1B): (1) nucleophilic α,α-difluororobenzylic
anions generated by two-electron reduction (e.g., using low-
valent metal or electrochemical reductions);6 (2) electrophilic
Received: July 18, 2021
Published: August 19, 2021
https://doi.org/10.1021/jacs.1c07459
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© 2021 American Chemical Society
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Figure 1. Selective functionalization of different C−F bonds and a selected example of a pharmaceutical bearing a ArCF2−Ar structural motif. (A)
Selective functionalization of different C−F bonds. (B) Selective functionalization of the C(sp3)−F bond in ArCF3. (C) Bond dissociation energies
(BDEs, calculated by DFT; see the Supporting Information) of C−F bonds. (D) Selected pharmaceutical bearing an ArCF2−Ar structural motif.
(E) Current excited-state palladium-catalyzed defluoroarylation of ArCF3.
in the resulting difluoroalkylated arenes (Figure 1C).8f To
date, only rare examples of transition-metal-mediated cleavage
of the C(sp3)−F bond in CF3 have been reported, through a
concerted oxidative addition process using nickel(0) com-
plexes.10 But the catalytic reaction involving such a process
leads to over-defluorination of all three C(sp3)−F bonds in
CF3. To overcome these daunting challenges, we hypothesized
a novel radical-involved oxidative addition strategy (Figure
1E). In this hypothesis, an excited-state palladium complex11 is
generated by irradiation of a ground-state palladium complex
with visible light, which then undergoes oxidative addition to
the C(sp3)−F bond in ArCF3, via a single-electron-transfer
(SET) pathway, to form an α,α-difluororobenzylic palladium-
(II) complex [ArCF2Pd(Ln)X] (A). Subsequently, the trans-
metalation of A with an arylmetal, followed by reductive
elimination, delivers the final product ArCF2−Ar. Herein, we
report this visible-light-induced palladium-catalyzed selective
defluoroarylation of ArCF3 with arylboronic acids, representing
the first example of selective carbofunctionalization of the
C(sp3)−F bond in CF3 through transition-metal-catalyzed
cross-coupling (Figure 1E). This novel catalytic system of an
excited-state palladium complex, without an exogenous
photocatalyst, shows unprecedented reactivity toward C-
(sp3)−F bond activation of (Het)ArCF3, while the previous
photoinduced palladium catalysts can only realize the trans-
formations of C(sp3)−Br or C(sp3)−I bonds.11a,d
RESULTS AND DISCUSSION
■
Accordingly, arylboronic acids were chosen as one of the
coupling partners for this reaction, because they are readily
available, are moisture insensitive, and are able to facilitate
transmetalation of ArCF2Pd(Ln)−F species by forming a
stronger B−F bond.4a,12 In a model coupling process, we found
that the catalytic mono-defluoroarylation can be achieved
through a combination of palladium catalyst Pd(tBu2PhP)2Cl2
and the bidentate phosphine ligand Xantphos under the
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irradiation of blue light (Table 1; for details, see the
Supporting Information, SI). The desired product, diary-
No defluoroarylation of the second CF3 group was observed
during the reaction process. Decreasing the loading amount of
1a from 6.0 equiv to 2.0 equiv led to a slightly lower yield of 3a
(51%) with increasing formation of over-defluorinated side
product 5a (entry 2). The use of equimolar equivalencies of 1a
and 2a significantly decreased the yield of 3a to 37% (entry 3).
Further optimization of the reaction conditions using one
more equivalent of 2a with KOH as the base could also
provide 3a in 51% yield (entry 4; for details, see Table S7).
The addition of an iridium photocatalyst to the reaction did
not improve the reaction efficiency (entry 5). Switching
Xantphos with DPEPhos or BINAP dramatically diminished
the yield (entries 6 and 7). Pd(PPh3)4 could also act as a
catalyst, but a lower yield (47%) was obtained (entry 8). The
sole use of Pd(PPh3)4 without Xantphos could lead to 3a in
22% yield (entry 9), and no 3a was observed with
Pd(PtBu2Ph)2 as the catalyst (entry 10). The absence of
palladium, Xantphos, or blue light totally shut down the
reaction (entries 11−13), demonstrating the essential role of
palladium, triarylphosphine, and blue light in promoting the
reaction. The moderate yield of 3a was obtained because of the
homocoupling of phenylboronic acid 2a and the formation of
over-defluorinated side product 5a from 3a. However, attempts
to increase the reaction efficiency by using different phenyl-
boronic acid esters failed. The formation of 5a is probably
ascribed to the identical reduction potential of starting material
1a and product 3a (Ep/2 for 1a/1a•− and 3a/3a•− are both
−2.68 V vs Fc+/Fc in MeCN) (see Figure 2), leading to the
SET reduction of 1a and 3a indiscriminately. As a result, the
over-defluorinated side product 5a was generated by a
sequential defluorodimerization from 3a. This is in sharp
contrast to previous reports for the hydrodefluorination and
defluoroalkylation of ArCF3 via a SET pathway,8 in which the
suppression of over-defluorinations took advantage of the
lower reduction potentials of the resulting aryldifluoromethy-
lated products than ArCF3, enabling the selective formation of
desired C−F bond functionalized products. We also examined
the dual nickel/photoredox catalytic system,13 but no desired
product was observed. Although a moderate yield of 3a was
obtained, this reaction trades off the overall yield loss from the
multistep synthesis of difluoroalkylating reagents.14 Most
importantly, this transformation fundamentally demonstrates
the feasibility of photoinduced palladium catalysis in the
selective activation of an inactive C(sp3)−F bond, thereby
paving a new way to access fluorinated compounds.
Table 1. Representative Results for the Optimization of the
a
Reaction Conditions
3a
4a
5a
b
c
b
entry
reaction conditions
“standard condition”
1a (2.0 equiv)
1a (1.0 equiv)
1a (1 equiv)
Ir(ppy)3 (1 mol %) was used
DPEPhos instead of Xantphos
BINAP instead of Xanphos
Pd(PPh3)4 instead of Pd(PtBu2Ph)2Cl2
Pd(PPh3)4 instead of Pd(PtBu2Ph)2Cl2 and
Xantphos
Pd(PtBu2Ph)2 instead of Pd(PtBu2Ph)2Cl2
and Xantphos
(%)
(%)
(%)
1
2
3
60
51
37
51
58
15
1
1
3
5
4
1
1
<1
4
6
8
7
4
5
3
1
2
nd
d
4
5
6
7
8
9
47
22
4
10
nd
nd
11
12
13
no [Pd]
no Xantphos
no light
nd
nd
nd
nd
nd
nd
a
Reaction conditions (unless otherwise specified): 1a (6 equiv), 2
(0.3 mmol, 1.0 equiv), THF (2 mL). The yield was determined by 19F
NMR using fluorobenzene as an internal standard. The yield was
calculated based on 2a. The yield was calculated based on 1a. nd, not
detected. 2 (2.0 equiv) was used, and KOH (2 equiv) instead of
b
c
d
K3PO4 (1.5 equiv).
ldifluoromethane 3a, was obtained in 60% yield (determined
by 19F NMR) from the reaction of 1,3-ditrifluoromethylben-
zene 1a (6.0 equiv) with phenylboronic acid 2a (1.0 equiv) in
the presence of Pd(tBu2PhP)2Cl2 (5 mol %), Xantphos (7.5
mol %), and a Bronsted base (K3PO4) under irradiation of blue
LED (12 W × 2) in tetrahydrofuran (THF) at 65 °C (entry 1).
With the viable reaction conditions in hand, we examined
the substrate scope of this visible-light-induced palladium-
Figure 2. Half-peak reduction potentials (Ep/2 vs Fc+/Fc in MeCN) of trifluoromethylarenes and diaryldifluoromethanes 3a.
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a
Scheme 1. Selective Defluoroarylation of Trifluoromethylarenes with Aryboronic Acids
a
Reaction conditions: 1 (6 equiv), 2 (0.3 mmol, 1.0 equiv), THF (2 mL). The yield was determined by 19F NMR using fluorobenzene as an
b
c
internal standard; the number given in parentheses is the isolated yield. Three equiv of 1 was used. 1 (1.0 equiv), 2 (2.0 equiv), and KOH (2
equiv) were used. The reaction was conducted on a 1 mmol scale: 1a (6.0 equiv), 2d (1.0 equiv), THF (6.7 mL).
d
catalyzed process (Scheme 1). Overall, the reaction of 1a with
a variety of arylboronic acids afforded the corresponding
defluoroarylated products 3a−3j in synthetically useful to
moderate yields. In the case of 3a, the low isolated yield is
because of its volatility. Trifluoromethylbenzenes bearing
different functional groups, such as methoxyl, alkyl chloride,
BocNH, PhMeN, and phenyl groups, were also applicable to
the reaction (3l−3r). Furthermore, heteroaryl-containing
substrates did not inhibit the reaction, with synthetically useful
yields obtained (3g, 3s, and 3t). However, aryl bromide
containing substrates were not a competent coupling partner,
due to their easy formation of cross-coupling products with
aryl boronic acids. The reaction can also be scaled up, as
demonstrated by the 1 mmol scale synthesis of 3d without
deterioration of the reaction efficiency. Additionally, the use of
1 equiv of trifluoromethylarene could also lead to comparable
yields (3a, 3c, 3d, 3f, 3i, 3j, 3n−3p, and 3r).
substrates 1u−1x, which possess similar reduction potentials
(Ep/2(1/1•−) = −2.60 to −2.27 V vs Fc+/Fc in MeCN) to 1a
and 1k−1t (Ep/2(1/1•−) = −2.68 to −2.55 V vs Fc+/Fc in
MeCN), were not applicable to the reaction (Figure 2),
suggesting that the suitable substrates should bear no electron-
withdrawing group that conjugates to the aromatic ring. These
findings are different from the previous photoredox-catalyzed
C−F bond functionalization of trifluoromethylarenes,8d,e in
which 1u−1x were suitable substrates, thus indicating that a
novel C−F bond activation mode of ArCF3 is involved in this
visible-light-induced palladium-catalyzed process. Trifluorome-
thylbenzene 1y and 1-methoxy-3-(trifluoromethyl)benzene 1z
were also examined, failing to provide the desired products. In
contrast, the corresponding substrates (1a and 1l) bearing the
second CF3 group on the aromatic ring could successfully
promote the reaction, due to the strong electron-withdrawing
effect of the additional CF3 group, which can increase the
reduction potential of the substrates, thus rendering them
more reactive to accept an electron for the C−F bond
activation via a SET pathway (Figure 2).
We also found that both the redox activity and substituents
on the aromatic ring of trifluoro(hetero)arenes are critical to
the reaction efficiency. Trifluoro(hetero)arenes 1a and 1k−1t,
which have reduction potentials Ep/2(1/1•−) ranging from
−2.68 to −2.27 V (vs Fc+/Fc in MeCN), are suitable
substrates. However, amide-, cyano-, and sulfonyl-containing
To gain mechanistic insight into this visible-light-induced
palladium-catalyzed process, we conducted several experiments
(Figure 3). 31P NMR monitoring of the reaction of 1a with 2a
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Figure 3. Mechanistic studies. (A) 31P NMR monitoring experiments of the palladium catalysts. (B) UV−vis absorption experiments in THF. (C)
Emission spectra of Pd(PPh3)4 and the mixture of Pd(PPh3)4 and Xantphos (irradiation at 450 nm). (D and E) Stern−Volmer luminescence
quenching of Pd(PPh3)4 by 1a. (F) Radical trapping experiments: (a) radical clock experiment, with the number given in parentheses being the
isolated yield; (b) EPR study of the reaction with PBN; (c) EPR spectra of 9. PdL4 = Pd(PPh3)4.
under standard reaction conditions in the absence of blue light
showed that two new palladium species, Pd(Xantphos)2
(A1)11g,15 and Pd(tBu2PhP)2 (A2),16 were formed during
the reaction process (Figure 3A). A1 and A2 still coexisted in
the reaction after irradiation. Complex A1 could also be
formed from the mixture of Pd(PPh3)4 with Xantphos (Figure
3A).17 Since A2 is not an active palladium catalyst for the
reaction (Table 1, entry 10), and the combination of
Pd(PPh3)4 with Xantphos could also provide the final product
3a (Table 1, entry 8), we supposed that A1 may be the active
species in promoting the reaction by forming an excited-state
palladium complex.11g To support this deduction, UV−vis
absorption experiments were conducted (Figure 3B), in which
Pd(PPh3)4 was used for the mechanistic studies because both
Pd(PPh3)4 and the combination of Pd(PPh3)4 with Xantphos
are active for the reaction (Table 1, entries 8 and 9). We found
that the combination of Pd(PPh3)4 with Xantphos caused a
bathochromic shift (Figure 3B), demonstrating that a new
palladium species was formed during the reaction process,
which is likely corresponding to A1. The addition of 1a and 2a
to the solution did not change the absorption band, and no
visible light absorption was observed for 1a, 2a, and Xantphos
(Figure 3B), thus excluding the possibility of forming a
donor−acceptor complex in the reaction. Additionally, orange-
red luminescence (λmax‑Em) at the wavelength of 572 nm in
THF was observed by combination of Pd(PPh3)4 with
Xantphos (Figure 3C). These results suggest that only the
Pd(0) complex was responsible for the absorption of blue light
(λ ≈ 450 nm), and palladium species A1 may serve as the
active catalyst for the formation of an excited-state palladium
complex. As for the role of A2, we proposed that it probably
acts as a Pd(0) catalyst reservoir to control the concentration
of the active catalyst, thus facilitating the overall catalytic cycle.
We also conducted Stern−Volmer luminescence quenching
experiments (Figure 3D and E) and found that the excited-
state [Pd(0)]* complex was efficiently quenched by trifluor-
omethylarene 1a. Finally, a radical clock experiment by using
α-cyclopropylstyrene 7 as a probe and electron paramagnetic
resonance (EPR) studies of the reaction of 1a and 2a with
spin-trapping agent phenyl tert-butyl nitrone (PBN) demon-
strated that an α,α-difluororobenzylic radical is involved in the
reaction (Figure 3F and Figures S29−S33). Additionally, the
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Scheme 2. Proposed Reaction Mechanism: (A) Proposed Mechanisms of [Pd(0)]*-Catalyzed C−F Bond Activation; (B)
Proposed Mechanism of Visible-Light-Induced Pd-Catalyzed Defluoroarylation of ArCF3 with Arylboronic Acids
EPR experiment showed that the absence of arylboronic acid
could also lead to spin adduct 9, suggesting that palladium
instead of arylboronic acid participates in the C−F bond
activation.
simultaneously. A is subsequently irradiated by visible light to
form excited-state palladium complex B.
On the other hand, the competitive photoinduced over-
defluorination/dimerization reaction can also occur after the
formation of 3, thus decreasing the yield of final product 3.
This deduction was supported by reaction of 3a with 2a under
standard reaction conditions, in which over-defluorinated 5a
was indeed generated (Scheme 3A). Furthermore, the real-
Based on the above results, a radical-involved C−F bond
oxidative addition mechanism is proposed. An α,α-difluoror-
obenzylic radical is generated by an excited-state [Pd(0)Ln]*
species though SET reduction of trifluoromethylarenes
(Scheme 2A, path A). According to the luminescence emission
of A1 and its cyclic voltammogram data, the oxidation
potential of excited-state A1* was calculated to be
Scheme 3. Mechanistic Studies of Generation of Over-
defluorinated Product 5
E
1/2([PdI]/[Pd0]*) = −2.76 V vs Fc+/Fc in THF (SI, Table
S8), which is able to reduce trifluoromethylarenes 1a and 1k−
1t (Ep/2(1/1•−) = −2.68 V to −2.55 V vs Fc+/Fc in MeCN).
For the inactivity of trifluoromethylarenes 1u−1x bearing an
electron-withdrawing group with a π-system conjugated to the
aromatic ring, we proposed that the coordination of
palladium(I) with the heteroatom (O or N) of the electron-
withdrawing group may result in an enolate-formed radical
anion,18 such as intermediate II, after SET reduction (Scheme
2A, path B). Compared to the sluggish C−F bond cleavage
process,19 this Pd(I)-stabilized trifluoromethylarene radical
anion II favors electron back-transfer and returns to the
ground-state Pd(0)Ln and trifluoromethylarene.8b
Overall, a plausible mechanism is depicted in Scheme 2B.
Trifluoromethylarene 1 undergoes single-electron reduction by
photoexcited [Pd(0)Ln]* (B) to generate α,α-difluororoben-
zylic radical III and [F-Pd(I)Ln] species C through C−F bond
cleavage. Subsequently, recombination of the resulting radical
with C leads to α,α-difluororobenzylic palladium complex
[ArCF2-Pd(II)FLn] (D). Meanwhile, radical III is able to
abstract hydride from solvent THF to produce ArCF2H 4,
which is not an intermediate en route to 3, because treatment
of ArCF2H 4 with arylboronic acids 2 under standard reaction
conditions failed to provide 3 (for details, see SI). Trans-
metalation of palladium complex D with arylboronic acid 2
produces key intermediate [ArCF2-Pd(II)Ln-Ar] (E), in which
the [Pd-F] species may facilitate the transmetalation step by
forming a [B-F] species.20 Finally, reductive elimination of E
delivers product 3 and regenerates palladium(0) catalyst A
time monitoring of reaction of 1a with 2a under standard
reaction conditions showed that compound 5a could not be
observed when a ∼30% yield of 3a was formed (Scheme 3B).
We also conducted an EPR experiment and found that a diaryl
monofluoromethyl radical IV was involved in the reaction
(Scheme 3C). These results suggest that an excited-state
palladium-catalyzed radical-involved defluorodimerization of 3
would be a possible pathway for the formation of 5 (Scheme
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2B), and the previously reported carbene-involved mechanism
via intermediate E seems unlikely.21 To identify the selectivity
of C−F bond activation between 1a and 3a, we conducted
kinetic studies and found that the initial rate of defluoroar-
ylation of 1a is 2.3 times faster than that of defluorodimeriza-
tion of 3a when the initial concentration of 1a is equal to the
initial concentration of 3a (Scheme 3D and Figure 4). This
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c07459.
■
sı
Experimental procedures, characterization of new
compounds, and computational details (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Xingang Zhang − Key Laboratory of Organofluorine
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 200032, China; orcid.org/0000-0002-4406-
6533; Email: xgzhang@mail.sioc.ac.cn
Authors
Yun-Cheng Luo − Key Laboratory of Organofluorine
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 200032, China
Fei-Fei Tong − Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, China
Figure 4. Kinetic studies of defluoroarylation of 1a (black line, 1a (0.5
equiv), 2a (1.0 equiv)) and defluorodimerization of 3a (red line: 3a
(0.5 equiv), 2a (1.0 equiv)).
Yanxia Zhang − Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, China
Chun-Yang He − Key Laboratory of Biocatalysis & Chiral
Drug Synthesis of Guizhou Province, Generic Drug Research
Center of Guizhou Province, Zunyi Medical University,
Zunyi, Guizhou 563003, China; orcid.org/0000-0002-
0599-7335
finding indicates that, although 1a and 3a possess identical
reduction potentials, these bond activations can be different
between 1a and 3a, depending on the deliberate control of
elementary steps in the catalytic cycle. To be specific, we can
increase the concentration of 1 to facilitate its SET reduction
by an excited-state palladium complex and/or fine-tuning the
reaction parameters (such as the base, the concentration of
arylboronic acid, and the ligand) that enables the faster rate of
formation of 3 from intermediate III than that of generation of
5 through dimerization of IV (Scheme 2B), thus increasing the
selectivity of C−F bond activation in ArCF3 over ArCF2-Ar. In
addition, the steric effect of 3a may also differentiate C−F
bond activation steps from the photoexcited Pd.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c07459
Notes
The authors declare no competing financial interest.
CONCLUSIONS
ACKNOWLEDGMENTS
■
■
Financial support for this work was provided by the National
Natural Science Foundation of China (21931013, 21790362)
and the Strategic Priority Research Program of the Chinese
Academy of Sciences (No. XDB20000000).
In conclusion, we have developed an unprecedented visible-
light-induced palladium-catalyzed process for selective C-
(sp3)−F bond arylation of trifluoromethylarenes with arylbor-
onic acids. The reaction proceeds under mild reaction
conditions and allows transformation of a variety of
arylboronic acids and trifluoromethylarenes. Mechanistic
studies reveal that the excited-state palladium complex induces
the C(sp3)−F bond oxidative addition via a SET pathway to
generate the α,α-difluororobenzylic palladium complex. This
novel visible-light-induced oxidative addition of a C−F bond
to a transition metal, without an exogenous photocatalyst,
opens a new chapter to access fluorinated compounds by
selective C(sp3)−F bond functionalization of readily available
and inexpensive fluorine sources through transition-metal-
catalyzed cross-couplings. The intriguing ability of the excited-
state palladium complex to activate inactive a C(sp3)−F bond
may also prompt the research area in palladium catalysis.
REFERENCES
(1) (a) Wang, J.; Sánchez-Roselló, M.; Acen
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