Dual Photoredox-/Palladium-Catalyzed Cross-Electrophile Couplings of Polyfluoroarenes with Aryl Halides and Triflates

Article abstract of DOI:10.1021/acs.organomet.0c00813

A visible-light photoredox-/Pd-catalyzed cross-electrophile arylation of polyfluoroarenes with aryl halides and triflates in the presence of dialkylamines is reported for the first time. This synergistic protocol affords access to a series of fluorodiaryls from easily available starting materials under mild and operationally simple conditions. A series of mechanistic experiments, including the stoichiometric reactions of a ligated (aryl)Pd complex, Stern-Volmer fluorescence quenching studies, cyclic voltammetry studies, and UV-vis spectroscopy, were performed to elucidate the potential catalytic pathway in this synergistic process.

Full text of DOI:10.1021/acs.organomet.0c00813

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Dual Photoredox-/Palladium-Catalyzed Cross-Electrophile Couplings
of Polyfluoroarenes with Aryl Halides and Triflates
Jian Qin,† Shengqing Zhu,† and Lingling Chu*
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ABSTRACT: A visible-light photoredox-/Pd-catalyzed cross-elec-
trophile arylation of polyfluoroarenes with aryl halides and triflates
in the presence of dialkylamines is reported for the first time. This
synergistic protocol affords access to a series of fluorodiaryls from
easily available starting materials under mild and operationally
simple conditions. A series of mechanistic experiments, including
the stoichiometric reactions of a ligated (aryl)Pd complex, Stern−
Volmer fluorescence quenching studies, cyclic voltammetry studies,
and UV−vis spectroscopy, were performed to elucidate the
potential catalytic pathway in this synergistic process.
control of chemoselectivity is leveraged by a selective single-
electron-transfer (SET) reduction of (aryl)NiII species rather
than (aryl)PdII species mediated by Zn on the basis of the
distinct properpties of nickel and palladium. Nevertheless, a
similar SET event of (aryl)PdII species, a common reactive
intermediate in numerous Pd-catalyzed aryl couplings, would
be interesting for exploiting new Pd-catalyzed transformations
yet remains elusive.
INTRODUCTION
■
Polyfluorobiaryls are prevalent motifs found in pharmaceut-
icals,1 catalysts, and ligands,2 as well as functionalized materials
including organic electronics3 and liquid crystals.4 Thereafter,
the development of efficient synthetic methods for the selective
construction of polyfluorobiaryls has attracted an increasing
research interest, with elegant progress having been achieved
during the past 20 years. Owing to the privileged properties of
palladium catalysts,5 Pd-catalyzed polyfluoroaryl−aryl cou-
plings represent one of the most efficient and widely employed
strategies to forge fluorobiaryls,6−8 where prefunctionalized
fluoroarenes6 (halides, benzoates, boronic acids, magnesium,
etc.) are generally employed for the control of reactivity and
selectivity. Alternatively, the acidic C−H bonds of fluoroarenes
can serve as more economical and attractive handles for Pd-
catalyzed cross-couplings with aryl nucleophiles or electro-
philes.7 Limited examples of C−F bonds of fluoroarenes, one
type of more readily available fluoroarenes, have been reported,
probably due to the challenges in the catalytic selective
activation of C−F bonds.8 Mechanistically, these Pd-catalyzed
polyfluoroaryl couplings proceed via a two-electron Pd(0)/
Pd(II) pathway. In this context, the development of a
mechanistically distinct mode for the Pd-catalyzed cross-
couplings of fluoroarenes under mild conditions would be of
particular interest.
On the other hand, metallaphotoredox catalysis11 offers a
distinct mode for cross-electrophile couplings with organic
reductants, through visible-light-induced single-electron trans-
fer of a transition-metal catalyst.12 The majority of known
transformations have focused on the C(sp2)−C(sp3) couplings
via photoredox/nickel dual catalysis, utilizing the high
reactivity of alkyl radicals. Herein, we report synergistic
phororedox- and palladium-catalyzed13,14 cross-electrophile
couplings of polyfluoroarenes with aryl halides and triflates
using an alkylamine as a stoichiometric reductant, forging
polyfluorobiaryls with exclusive para selectivity under opera-
tionally simple and mild conditions. This photoredox/
palladium protocol was inspired by the photoinduced SET
C−F activation of polyfluoroarenes developed by Weaver and
others15 and complements the previously reported photo-
induced SNAr arylation of polyfluoroarenes,15a,b where
electron-rich arenes were employed. During the preparation
of this paper, Rueping and co-workers reported a photoredox-/
Catalytic cross-electrophile couplings between two electro-
philes in the presence of a stoichiometric reductant (Zn, Mn,
etc.), which preclude the use of organometallic agents by
directly utilizing benign and abundant electrophiles, represent
an attractive and practical platform for the construction of C−
C bonds.9 Recently, Weix and co-workers have successfully
achieved the selective cross-electrophile couplings between two
aryl electrophiles to forge valuable diaryls through nickel and
palladium multimetallic catalysis.10 In this manifold, excellent
Special Issue: Organometallic Solutions to Challenges
in Cross-Coupling
Received: December 29, 2020
https://dx.doi.org/10.1021/acs.organomet.0c00813
© XXXX American Chemical Society
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A

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a
nickel-catalyzed reductive arylation of polyfluoroarenes (Figure
Table 1. Optimizations of Reaction Conditions
1).12e
entry
variation from the standard conditions
yield (%)
b
1
none
85 (78)
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Pd(OAc)2, instead of [PdCl(allyl)]2
Pd(PPh3)4, instead of [PdCl(allyl)]2
PdCl2(PPh3)2, instead of [PdCl(allyl)]2
dppe instead of dppBz
dppm instead of dppBz
dppp instead of dppBz
DIPEA, instead of Cy2NH
Et3N, instead of Cy2NH
(i-Pr)2NH, instead of Cy2NH
without PC
without [PdCl(allyl)]2
without dppBz
without Cy2NH
without Na2CO3
in the dark
trace
trace
trace
66
34
9
15
32
71
8
trace
16
trace
7
ND
a
Reaction conditions: Reaction conditions: Ir(ppy)3 (2 mol %),
[PdCl(allyl)]2 (7 mol %), dppBz (7 mol %), fluoropyridine (0.2
mmol), ArBr (2.0 equiv), Cy2NH (0.5 equiv), Na2CO3 (2.0 equiv),
DMA [0.05 M], 70−75 °C, 20 h. Yields were determined by GC
using dodecane as the internal standard. Abbreviations: dppe = 1,2-
bis(diphenylphosphino)ethane, dppm = bis(diphenylphosphino)-
b
methane, dppp = 1,3-bis(diphenylphosphino)propane. Isolated
yields.
Figure 1. Catalytic fluoroaryl−aryl couplings for the construction of
polyfluorodiaryls.
their bite angles affected the reaction efficiency and dppBz
proved to be optimal (entries 5−7). With regard to the
stoichiometric reductants, we found that, in the presence of
inorganic bases such as Na2CO3, secondary sterically hindered
amines such as Cy2NH and i-Pr2NH performed better than
common tertiary amines (e.g. (i-Pr)2NEt and Et3N) (entries
8−10). Control experiments indicated that the palladium
catalyst, reductant, and visible light were essential to this cross-
electrophile coupling of fluoroarenes, as no products formed in
the absence of any of them (entries 12, 14, and 16), while low
yields were still obtained in the absence of a photocatalyst or a
ligand (entries 11 and 13). For nonoptimal conditions,
hydrodebromination and self-couplings of aryl bromides were
the major side reactions observed in this photoredox/Pd
system.
With the optimized conditions in hand, we turned our
attention to exploring the generality of this synergistic
photoredox/Pd cross-electrophile diaryl coupling. Under the
optimal conditions, as depicted in Scheme 1, an array of aryl
bromides incorporating electron-donating and electron-with-
drawing substituents showed moderate to good efficiency in
this protocol (products 3a−o). The electronic property of aryl
RESULTS AND DISCUSSION
■
We began our investigations by employing methyl 4-
bromobenzoate (1a) and pentafluoropyridine (2a) as model
substrates (Table 1). Pleasingly, we found that the
combination of Ir(ppy)3 as the photocatalyst, allylpalladium-
(II) chloride dimer [PdCl(allyl)]2 as the catalyst, 1,2-
bis(diphenylphosphino)benzene (dppBz) as the ligand,
dicyclohexylamine (Cy2NH) as the reductant, and Na2CO3
as the base could enable the selective diaryl coupling of 1a and
2a to afford fluorodiaryl product 3a in 85% GC yield (entry 1).
Intriguingly, the choice of palladium catalysts played a crucial
effect on the coupling efficiency, as switching to other
commonly employed Pd(II) catalysts or Pd(PPh3)4, which
has typically been used in photoinduced Pd-catalyzed trans-
formations,13 led to almost no formation of product 3a (entries
2−4).
Bidentate bis-phosphine ligands were the most effective
ligand skeletons to promote the desired cross-couplings, while
B
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a
product 3f. Nonetheless, iodoarenes failed due to a facile self-
coupling process under the photoinduced conditions. Pleas-
ingly, the reaction of naphthyl bromide gave the desired
fluorodiaryl product 3m in moderate yield. Moreoever, bromo
heteroarenes, represented by benzimidazoles and carbazoles
that are privileged skeletons present in many bioactive natural
products and pharmaceuticals, were competent coupling
partners in this synergistic protocol, delivering the desired
heteroaryl products in moderate yields (products 3n,o). With
regard to the ployfluoroarene component, a para-trifluorome-
thylated fluoroarene was a suitable substrate, undergoing
selective cross-electrophile couplings with aryl bromides in
synthetically useful yields (products 3p−r). Nevertheless,
other polyfluoroarenes suffered from low efficiency (3s).
In comparison with aryl bromides, aryl triflates can be easily
prepared from more economical phenols. Under this dual
photoredox/Pd protocol with 1,4-dicyanobenzene as a
cophotocatalyst and LiI as an additive,13d we were pleased to
find that aryl triflates were capable of undergoing selective
cross-electrophile coupling with a fluoroarene with moderate
efficiency (Scheme 2). Aryl triflates bearing electron-donating
Scheme 1. Scope of Aryl Bromides and Fluoroarenes
a
Scheme 2. Scope of Aryl Triflates
a
Reaction conditions: Ir(ppy)3 (2 mol %), 1,4-dicyanobenzene (5
mol %), [PdCl(allyl)]2 (7 mol %), dppBz (7 mol %), fluoropyridine
(0.2 mmol), ArOTf (1.5 equiv), Cy2NH (0.8 equiv), Na2CO3 (2.0
equiv), LiI (0.3 equiv), DMA [0.05 M], 70−75 °C, 20 h.
or electron-neutral substituents demonstrated good reactivity
(products 3b,d,t−w). Nonetheless, electron-deficient aryl
triflates were incompetent coupling partners in the current
conditions.
a
Reaction conditions: Ir(ppy)3 (2 mol %), [PdCl(allyl)]2 (7 mol %),
dppBz (7 mol %), fluoroarene (0.2 mmol), ArBr (2.0 equiv), Cy2NH
(0.5 equiv), Na2CO3 (2.0 equiv), 70−75 °C, DMA [0.05 M], 20 h.
Isolated yields are given.
To elucidate the potential reaction pathway of this
photoredox/Pd dual protocol, several mechanistic studies
have been performed, as depicted in Scheme 3. Addition of
the radical inhibitor TEMPO to the standard conditions
completely shut down the desired cross-couplings, while the
addition of stoichiometric amount of butylated hydroxytoluene
(BHT) had no dramatic effect on the coupling efficiency
(Scheme 3A). In this case, we also observed a small amount of
the hydrodefluorinated pyridine 4, the 19F NMR yield of which
increased to 38% with the addition of 5.0 equiv of BHT in the
absence of aryl bromide (Scheme 3A). Furthermore,
bromides was found to have some effect on the cross-coupling
efficiency, and electron-deficient bromoarenes generally
exhibited higher efficiency than electron-rich bromoarenes.
The mild conditions were compatible with various functional
groups including ethers, esters, halogens, ketones, and silanes
(products 3a,d−l). For multihaloarenes, exclusive chemo-
selectivity toward bromides was observed, as exemplified by
C
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Scheme 3. Mechanistic Studies: (A) Radical Inhibition Reaction; (B) Reactions in the Presence of Alkenes; (C) Stoichiometric
and Catalytic Reactions with Pd(II) Complex; (D) Stern−Volmer Fluorescence Quenching Studies; (E) Cyclic Voltammetry
of Pd(II) Complex; (F) UV−Vis Spectroscopy of the Reaction Mixture
subjection of alkenes, such as 4-phenyl-1-butene (5), into the
template reaction led to a dramatic decrease in the yield of
product 3a, together with major formations of the hydro-
arylation product and the Heck-type product, while no
fluoroarene−olefin coupling products were detected via the
analysis of crude GC-MS (Scheme 3B). Next, the ligated Ar-
Pd(II) complex 6 was prepared according to a previous
procedure.16 The stoichiometric reaction of Ar-Pd(II) 6 with
pentafluoropyridine (2a) in the presence of Ir(ppy)3 and
Cy2NH led to the formation of the desired fluorodiaryl 3h in
30% 19F NMR yield, together with a 33% yield of the
hydrodefluorinated pyridine 4; reaction of aryl bromide with
2a with a catalytic amount of complex 6 also resulted in 16% of
fluorodiaryl 3h (Scheme 3C). These results, along with the
aforementioned Heck-type products, indicated that Ar-Pd(II)
could be a reactive intermediate for this reductive aryl
coupling.
visible absorption spectrum of the reaction mixture exhibited
a strong absorption at 275 nm that was different from those of
Ar-Pd(II) complex 6 or the [PdCl(allyl)]2 catalyst, indicating
that a new [Pd] species could be involved in the reaction
process (Scheme 3F). Nonetheless, trials for monitoring the
stoichiometric reaction of Ar-Pd(II) complex 6 with Ir(ppy)3
and light in the absence of fluoroarenes via 31P NMR failed,
probably due to the instability of [Pd] species.
On the basis of the above experimental results, a plausible
mechanism was proposed (Scheme 4). Oxidative addition of
Pd(0) with aryl bromide could form Ar-Pd(II) intermediate B
(E1/2[Pd(II)/ Pd(I)] = −0.44 V vs SCE in DMA), which could
undergo a SET event with the photoexcited *Ir(III) species II
(E1/2[IrIII*/IrIV] = −1.73 V vs SCE in MeCN)18 to generate
Ar-Pd(I) intermediate C and Ir(IV). At the same time, a SET
event between the photoexcited *Ir(III) and fluoroarene
would generate the radical anion species D. At this juncture,
Ar-Pd(I) intermediate C would intercept the fluoroarene
radical anion D to form the Ar-Pd(II)-(ArFn−1) intermediate
E, which subsequently could undergo reductive elimination to
furnish the fluorodiaryl product, along with the regeneration of
Pd(0) to close the palladium cycle. Meanwhile, the Ir(IV)
species III would oxidize the reductant amine to regenerate the
ground state of Ir(III) to complete the photocatalyst cycle.
With respect to the reduction of fluoroarene, a tandem
catalytic cycle enabled by the reducing Ir(II) species might be
operative.19 We also cannot exclude the reaction pathway via
interception of radical anion D by Ar-Pd(II) B at this stage.
Furthermore, Stern−Volmer fluorescence quenching studies
were conducted, and the results showed that the photoexicited
state of *Ir(III) can be efficiently quenched by Ar-Pd(II)
complex 6, rather than by amine Cy2NH with or without
Na2CO3; on the other hand, pentafluoropyridine showed a
comparatively weak quenching effect on the photocatalyst,
suggesting that the oxidative quenching of *IrIII by
pentafluoropyridine could also occur (Scheme 3D). These
quenching results were also consistent with their electro-
chemical behaviors. Cyclic voltammetry studies indicated that
the half-redox potential of Ar-Pd(II) complex 6 (E1/2[Pd(II)/
Pd(I)] = −0.44 V vs SCE in DMA) was lower than that of
pentafluoropyridine (C5F5N; E1/2 = −2.12 V vs SCE);17
red
CONCLUSION
■
therefore, the SET reduction of Ar−Pd(II) by *IrIII should be
much more thermodynamically favorable than that of
pentafluoropyridine (Scheme 3E). Additionally, the UV−
In summary, we have developed a mild and efficient protocol
for cross-electrophile arylation of polyfluoroarenes via visible-
light photoredox and palladium dual catalysis, enabling
D
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Engineering and Biotechnology, Donghua University,
Shanghai 201620, People’s Republic of China
Scheme 4. Proposed Pathway
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.0c00813
Author Contributions
†J.Q. and S.Z. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21702029, 21901036), the Shanghai Sailing Program
(19YF1400300), and the Fundamental Research Funds for
the Central Universities for financial support.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
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Experimental procedures, characterization of com-
pounds, and mechanistic experiments (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
Lingling Chu − State Key Laboratory for Modification of
Chemical Fibers and Polymer Materials, Center for Advanced
Low-Dimension Materials, College of Chemistry, Chemical
Engineering and Biotechnology, Donghua University,
Shanghai 201620, People’s Republic of China; orcid.org/
0000-0001-7969-0531; Email: lingling.chu1@dhu.edu.cn
́
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Authors
Jian Qin − State Key Laboratory for Modification of Chemical
Fibers and Polymer Materials, Center for Advanced Low-
Dimension Materials, College of Chemistry, Chemical
Engineering and Biotechnology, Donghua University,
Shanghai 201620, People’s Republic of China
Shengqing Zhu − State Key Laboratory for Modification of
Chemical Fibers and Polymer Materials, Center for Advanced
Low-Dimension Materials, College of Chemistry, Chemical
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