Synthesis of unsymmetrical biaryl ethers through nickel-promoted coupling of polyfluoroarenes with arylboronic acids and oxygen

Article abstract of DOI:10.1039/c2cc33755j

Polyfluoro-substituted unsymmetrical biaryl ethers were synthesized via a novel Ni-catalyzed cross-coupling reaction of polyfluoroarenes with arylboronic acids and oxygen. The polyfluorinated arenes presumably captured the phenoxide intermediate efficiently, which made the oxygen-insertion proceed smoothly via the S_NAr protocol. The ¹⁸O labeling experiment demonstrated that the oxygen introduced into unsymmetrical diaryl ether originated from very trace amounts of oxygen in the reaction system. A plausible mechanism was also suggested.

Full text of DOI:10.1039/c2cc33755j

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COMMUNICATION
Synthesis of unsymmetrical biaryl ethers through nickel-promoted
coupling of polyfluoroarenes with arylboronic acids and oxygenw
Jian Zhang, Jingjing Wu, Yang Xiong and Song Cao*
Received 26th April 2012, Accepted 6th July 2012
DOI: 10.1039/c2cc33755j
Polyfluoro-substituted unsymmetrical biaryl ethers were synthesized
via a novel Ni-catalyzed cross-coupling reaction of polyfluoroarenes
with arylboronic acids and oxygen. The polyfluorinated arenes
presumably captured the phenoxide intermediate efficiently, which
Scheme 1 Synthesis of polyfluoro-substituted unsymmetrical biaryl ethers.
made the oxygen-insertion proceed smoothly via the SNAr
protocol. The 18O labeling experiment demonstrated that the
oxygen introduced into unsymmetrical diaryl ether originated
from very trace amounts of oxygen in the reaction system.
A plausible mechanism was also suggested.
(such as ArOꢀ, RSꢀ, BuLi, etc.) by aromatic nucleophilic
substitution (SNAr) has received increasing attention for the
synthesis of functionalized aromatic compounds.8 Herein, we report
a novel and practical synthesis of polyfluoro-substituted unsym-
metrical biaryl ethers via nickel-catalyzed oxidative hydroxylation
of arylboronic acids, followed by SNAr reaction with polyfluori-
nated arenes under an argon atmosphere (Scheme 1).
The chemistry of arylboronic acids continues to be a growth area
in synthetic methodology.1 The palladium-catalyzed Suzuki
cross-coupling of arylboronic acids with aryl halides is one of
the most popular methods to prepare unsymmetrical biaryls.2 It
is well-known that except for normal cross-coupling products,
the homo-coupling product and phenol are often obtained as
by-products in Suzuki reaction.3 Nowadays, these unwanted
side reactions have been developed as useful methods for the
synthesis of symmetrical biaryls or phenol under different reaction
conditions, respectively.4 On the other hand, unsymmetrical and
symmetrical biaryl ethers can be prepared by the Pd, Rh, Cu
catalyzed C–O coupling reactions of arylboronic acids with
pyridotriazol-1-yloxy heterocycles, electron-deficient nitroarenes,
phenols in the presence of pure dioxygen, air or hydrogen
peroxide, respectively.5 In addition, Liu and Robins reported that
the 6-fluoropurine nucleoside derivatives can be used as coupling
partners in Ni-catalyzed cross-coupling with arylboronic acids.6
They indicated that in addition to normal cross-coupling products,
the trace oxygen-insertion byproduct was also detected. This is the
only one example of C–O coupling reaction of arylboronic acids
with aryl fluorides for the formation of unsymmetrical biaryl ether
which was identified as minor impurity by authors.
The activation and functionalization of strong carbon–
fluorine bonds by transition metals have been of great importance
in organometallic chemistry and catalyst development in recent
years.9 But the catalytic cross-coupling of aryl fluorides has received
less attention than that of other aryl halides.10 Furthermore,
only limited examples for the catalytic cross-coupling of poly-
fluoroarenes have emerged. For example, Schaub and Radius
reported the catalytic C–F activation of perfluoroarenes in the
presence of a Ni–NHC complex for Suzuki-type cross-coupling
reactions.11 However, drawbacks of these contributions are
that they require highly unusual, complicated and air sensitive
metal catalysts.
During the course of our recent activation and functionalization
of carbon–fluorine bonds in octafluorotoluene 1a with phenyl-
boronic acid 2a in the presence of NiCl2(PCy3)2 under an argon
atmosphere, in addition to normal cross-coupling product 5a
(30%, Table 1, entry 3) and homo-coupling byproduct 4a
(15%), an unexpected substantial amount of oxygen-insertion
byproduct 3a was also obtained (54%). Intrigued by this experi-
mental observation, we decided to examine the unusual reaction
in detail. Initially, reaction of 1a and 2a was used as a model
system to investigate the reaction conditions for the synthesis of
unsymmetrical biaryl ether 3a (Table 1, and Table SA (see ESIw)).
As expected, in the absence of the metal catalyst, the reaction
could not proceed even after prolonged reaction time (entry 1).
Among various types of Ni and Pd catalysts tested, Ni(acac)2
exhibited excellent catalytic activity in C–O coupling reaction. The
cross and homo-coupling reactions were sufficiently suppressed
and the SNAr reaction of 1a with the phenoxide proceeded
smoothly (entry 10). Other Ni and Pd complexes also showed
some activity but afforded a mixture of Suzuki cross-coupling
Nowadays the perfluoro- or polyfluoro-containing diaryl ethers
have gained real interest especially in the materials science,
pharmaceutical and agricultural areas due to their unique chemical
and physiological properties.7 The replacement of fluorine
atoms on an electron-deficient aromatic ring with nucleophiles
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy,
East China University of Science and Technology, Shanghai, 200237,
China. E-mail: scao@ecust.edu.cn; Fax: +86 21 64252603;
Tel: +86 21 64253452
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc33755j
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 8553–8555 8553

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Table 1 Reaction of octafluorotoluene 1a with phenylboronic acid 2a
in the presence of various catalystsa
the desired O-arylated polyfluoroarenes were obtained in high
yields. It was found that highly electron-deficient polyfluoro-
arenes could easily afford the biaryl ethers, however, mono-
fluorobenzene, 1,3,5-trifluorobenzene and 1,4-difluorobenzene
could not react with phenylboronic acids.
A review of the literature indicated that some examples have
been reported to prove the origin of the oxygen in unsymmetrical
diaryl ethers or phenol when the reactions involved phenylboronic
acids.3,12 18O2 and H218O were used to probe where the oxygen
came from. Their results suggested that the oxygen that
incorporated ether originated partially from O2 or H2O,
respectively, under different reaction conditions.5d,e,12 Their
experiments also disclosed that the key intermediate phenol
can serve as a substrate to undergo O-arylation.5d,e However,
these reactions were performed in the presence of dioxygen, air
or water. In our case, the reaction was performed under
anhydrous and oxygen-free conditions. It seems that the ether
oxygen in unsymmetrical diaryl ethers (or phenol) is derived
from phenylboronic acids. Thus we tried to probe where the
oxygen atom that introduced into diaryl ether or phenol came
from in the next section.
Entry
Catalyst
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
—
NiCl2
No reaction
3a : 4a = 58 : 42
3a : 4a : 5a = 54 : 15 : 30
No reaction
3a : 4a = 36 : 60
3a : 4a = 50 : 47
3a : 4a = 58 : 39
3a : 4a = 30 : 66
3a : 4a = 30 : 68
3a = 92
NiCl2(PCy3)2
NiCl2(PPh3)2
NiCl2(dppe)
NiCl2(dppp)
Ni(cod)2
Pd(PPh3)4
Pd(P(t-Bu)3)2
Ni(acac)2
a
All catalysts and bases are anhydrous, solvents are dried by the
b
standard method prior to use. Yield determined by GC analysis.
product 5a, homo-coupling product 4a and oxygen-insertion
product 3a.
At the outset, phenylboronic acid 2a was treated with 5 mol%
of Ni(acac)2 and K3PO4 in THF reflux for 12 h without the
addition of octafluorotoluene 1a, the homocoupling reaction was
found to hardly proceed and gave a mixture of homocoupling
product 4a, phenyl boroxine 6 and phenol 7 (20 : 60 : 10). The
yield of homocoupling product 4a was much lower due to the
absence of sufficient amounts of oxidant (Scheme 2, eqn (1)).
The preliminary experiment indicated that the driving force for the
formation of biaryl ether 3a might be the capture of phenoxide
(PhOꢀ) by octafluorotoluene.
Next, our efforts were directed towards the evaluation of the
influence of solvents and bases on the model reaction using the
Ni(acac)2 as the catalyst (Table SA, see ESIw). The results revealed
that K3PO4 and THF can be used as the most suitable base and
solvent, respectively. In the absence of a base, the reactivity was
attenuated significantly and the starting materials were almost
quantitatively recovered. Summarizing these experimental results,
we observed that in the presence of 5 mol% of Ni(acac)2 and
2 equiv. of K3PO4, oxygen-insertion took place in THF at reflux
under argon for 11 h leading to the diaryl ether in 92%.
With the optimized reaction conditions in hand, we set out
to define the generality and scope of the method, a variety of per- or
polyfluoroarenes and substituted arylboronic acids were examined
under the optimized conditions (Table 2). Substituted arylboronic
acids afforded high to excellent yields of the unsymmetrical biaryl
ethers irrespective of electronic effects. The synthesis of 3g is
particularly interesting. It implied that this method can be expanded
to prepare some special fluorine-containing unsymmetrical biaryl
ethers when phenol is unstable or unavailable. In most cases,
In order to elucidate the source of oxygen in the biaryl ether
and phenol, several additional experiments were performed
(see Scheme SA–SE, ESIw). These results proved that the
oxygen atoms of biaryl ethers and phenol originated neither
from water nor from phenylboronic acids.
On the basis of our experimental results, we suggested that
the oxygen atoms of biaryl ethers and phenol were derived
from the very trace amounts of oxygen in the reaction system.
Although all reagents and solvents were dried and degassed
prior to use, and the reactions were performed under an argon
atmosphere using oven-dried glassware, nevertheless, very
trace amounts of oxygen were still present in our argon gas
or solvents. The oxygen acted as an oxidant and promoted the
formation of phenoxide in the presence of Ni(acac)2.
Table 2 Scope of polyfluoroarenes and arylboronic acidsa,b
To confirm our assumptions, reactions of octafluorotoluene
1a and phenylboronic acid 2a with different amounts of
oxygen or 18O2 were performed in the presence of 5 mol%
of Ni(acac)2 and 2 equiv. of K3PO4 (Scheme 3). When the
reaction was carried out in an argon atmosphere where very
trace amounts of oxygen exist in the reaction system, the
highest yield of the biaryl ether (3a) was obtained (91%).
a
5 mol% of Ni(acac)2, 2 equiv. of K3PO4, THF, reflux, argon.
Isolated yield.
b
Scheme 2 Homocoupling reaction of phenylboronic acid 2a with
5 mol% of Ni(acac)2 under an argon atmosphere and 18O2.
c
8554 Chem. Commun., 2012, 48, 8553–8555
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two intermediates, IV and HOOB(OH)2 V. If the reaction is
performed in the presence of highly electron-deficient fluorinated
aromatic compounds, V can further hydrolyze to the key inter-
mediate, hydrogen peroxide VI, which reacts easily with aryl-
boronic acids to afford phenol VII. Finally, nucleophilic attack
of fluoroarenes by phenoxide could generate the biaryl ether
VIII, whereas IX was detected as a minor product.
In conclusion, we described a novel and efficient method for
the synthesis of polyfluoro-substituted unsymmetrical biaryl
ethers via oxygen-promoted Ni-catalyzed coupling of arylboronic
acids with polyfluoroarenes. The very trace amount of oxygen in
the reaction system is enough to complete the reaction and the
oxygen acts as an efficient Ni(II) oxidant. The highly electron-
deficient per- or poly-fluorinated aromatic compounds served as
efficient trapping agents of phenols generated in situ from
phenylboronic acid and Ni(acac)2.
Scheme 3 Reaction of 1a and 2a with different amounts of oxygen or
18O2 with 5 mol% of Ni(acac)2 and K3PO4.
This work was supported by the National Natural Science
Foundation of China (Grant No. 21072057), 973 Program
(2010CB126101), the twelfth five-year plan period of China
(2011BAE06B01-15), and 863 Program (2011AA10A204).
Scheme 4 Possible mechanism for oxygen-promoted Ni-catalyzed
coupling reaction.
However, when this Ni-catalyzed reaction was directly performed
under aerobic conditions, the yield of 3a decreased obviously
(75%), whereas the amount of homocoupling product 4a (15%)
increased due to the existence of a small amount of water in air. If
the reaction is conducted under an oxygen atmosphere, care should
be taken to avoid undue exposure to air, the desired product 3a was
produced in good yield (85%). Finally, when dioxygen was replaced
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by 18O2, much to our delight, O-labeled biaryl ether 3a0 was
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The 18O-labeling experiment clearly indicated that the oxygen
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 8553–8555 8555