Pd(OAc)2-catalyzed oxidative C-H/C-H cross-coupling of electron-deficient polyfluoroarenes with simple arenes

Article abstract of DOI:10.1021/ja109383e

Pd(OAc)₂-catalyzed intermolecular C-H/C-H cross-coupling reactions between electron-deficient polyfluoroarenes and simple arenes for the synthesis of fluorinated biaryls have been developed. Deuterium-labeling experiments suggested that C-H bon

Full text of DOI:10.1021/ja109383e

Published on Web 10/27/2010
Pd(OAc) -Catalyzed Oxidative C-H/C-H Cross-Coupling of Electron-Deficient
2
Polyfluoroarenes with Simple Arenes
Ye Wei and Weiping Su*
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese
Academy of Sciences, Fuzhou, Fujian 350002, China
Received September 12, 2010; E-mail: wpsu@fjirsm.ac.cn
relatively electron-rich arylpalladium complex should be more facile
Abstract: Pd(OAc)
2
-catalyzed intermolecular C-H/C-H cross-
2c,8
than that of the simple arene.
2
Herein, we describe the Pd(OAc) -
coupling reactions between electron-deficient polyfluoroarenes
and simple arenes for the synthesis of fluorinated biaryls have
been developed. Deuterium-labeling experiments suggested that
C-H bond cleavage of the simple arenes rather than the
polyfluoroarenes is involved in the rate-limiting step.
catalyzed oxidative cross-coupling reactions of diverse electron-
deficient polyfluoroarenes with benzene and substituted benzenes.
This novel transformation produces fluorobiphenyls, which are of
9
10
great importance in pharmaceutical and materials applications,
with high chemoselectivity.
Over the past decade, significant progress has been achieved in
transition-metal-catalyzed direct aromatic C-H arylation in which
a preactivated arene is required as the second coupling partner (eqs
1
,2
1
and 2 in Scheme 1). However, a far more efficient approach
Initially, the reaction of pentafluorobenzene (1) with benzene
(2) was chosen as a model reaction for optimization of the reaction
conditions (eq 4; see the Supporting Information for detailed
to nonsymmetrical biaryls would be direct oxidative cross-coupling
between two non-preactivated arenes (eq 3 in Scheme 1). In this
context, a few groups have recently reported their pioneering studies
directed toward cross-coupling reactions between heteroarenes and
results). Preliminary results indicated that with the use of Cu(OAc)
(2 equiv) as an oxidant, K CO (2 equiv) as a base, and Pd(OAc)
2
3
4
arenes or heteroarenes, between directing-group-containing arenes
2
3
2
5
6
and arenes, and between two simple arenes. Despite these
advances, the reported reactions are still restricted to a narrow
substrate scope. Clearly, such a dual C-H activation strategy will
only be widely accepted and used in organic synthesis by synthetic
chemists when a broad spectrum of (hetero)arenes can be utilized
as coupling partners with high efficiency.
(10 mol %) as a catalyst, the reaction carried out in dimethylac-
etamide (DMA) at 110 °C for 24 h afforded the desired product 3a
in 65% yield. After screening different bases, we found that CsOPiv
(1.5 equiv) gave 3a in 74% yield. Furthermore, replacing CsOPiv
2 3
with the combination of Cs CO (0.75 equiv) and PivOH (1.5 equiv)
gave a comparable yield (72%). Interestingly, other carboxylic acids
such as AcOH were observed to be inferior to PivOH, which could
be explained by the formation of more soluble CsOPiv. Although
an acidic reaction medium has been observed to be beneficial to
Scheme 1. Methods for Biaryl Construction
5c
metal-mediated C-H cleavage, PivOH merely acted as the source
of CsOPiv in this reaction, as evidenced by the fact that the
combination of PivOH and Cs
yield as CsOPiv. Finally, when Na
Cs CO , an 83% yield was obtained, showing the effect of the metal
2
CO
3
gave rise to essentially the same
One of the great challenges posed by the arene cross-coupling
method is controlling the reaction chemoselectivity to avoid the
2
CO was used in place of
3
7
2
3
unwanted homocoupling byproduct. Inspired by the previously
1
1,12
3-6
counterion of the base on the reaction.
Notably, only trace
reported arene cross-coupling reactions,
we envisioned that Pd-
amounts of biphenyl and decafluorobiphenyl byproducts generated
from homocoupling of the corresponding arenes were detected under
the optimized conditions. Other commonly used oxidants such as
catalyzed selective cross-coupling between two electronically
distinctly different arenes could be achieved under suitable reaction
conditions. The difference between the reactivities of the two arenes
toward C-H cleavage/palladation would be capable of governing
the precise sequence of two palladation steps in the catalytic cycle
to selectively form the Pd intermediate containing the two cross-
coupling fragments Pd(Ar)(Ar′), which is the key to achieving
2
Ag(I) salts, benzoquinone, and O proved to be either less effective
or totally ineffective. Although the experiments for optimizing the
reaction conditions were conducted with the strict exclusion of
moisture using a glovebox, further investigation showed that such
strict reaction conditions were not necessary for this reaction.
3
a
selective cross-coupling. For the reaction system consisting of
polyfluorobenzene and simple arene, we hypothesized that the
palladation of the more electron-rich simple arene would occur in
the first step of catalytic cycle because of the stronger interaction
between the simple arene and the Pd catalyst (i.e., the Pd-CAr
interaction), which would contribute to the lowering of the free
With the optimal conditions in hand, we next examined the
substrate scope with respect to the polyfluoroarene. As depicted in
Scheme 2, tetrafluoroarenes containing additional substituents
furnished fluorinated biaryls in moderate to good yields (3a-j).
1,2,3,5-Tetrafluorobenzene and 1,2,4,5-tetrafluorobenzene, each of
which possesses two potential reaction sites, generated mixtures
of mono- and diarylation products (3k + 3k′ and 3l + 3l′) in 56
and 51% overall yield, respectively. 2,3,5,6-Tetrafluoropyridine also
participated in this reaction in 70% yield. 1,3,5-Trifluorobenzene
8
energy of activation in the C-H cleavage process. In the second
palladation step, however, the more electron-deficient polyfluo-
robenzene would predominate over the simple arene because the
reaction of the more electron-deficient polyfluorobenzene with the
10.1021/ja109383e  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 16377–16379 9 16377

C O M M U N I C A T I O N S
Scheme 2. Scope of Polyfluoroarenes in Pd(OAc)
2
-Catalyzed
Scheme 4. Intermolecular Kinetic Isotope Effect
a
Oxidative Arylation
of the kinetic isotope effects (KIEs) for both coupling partners
(
2
Scheme 4). An intermolecular competition reaction between
,3,5,6-tetrafluoroanisole and deuterated 2,3,5,6-tetrafluoroanisole
showed a KIE of 1.3 (eq 5 in Scheme 4; see the Supporting
Information for detailed experimental procedures), illustrating that
the rate-limiting step does not involve the C-H cleavage of the
polyfluorobenzene. However, primary KIEs of 6.5 and 4.8 were
observed for benzene (eq 6 in Scheme 4) and 1,2-dichlorobenzene
(eq 7 in Scheme 4), respectively (see the Supporting Information
for detailed experimental procedures). These results indicate that
the C-H bond cleavage of simple arenes is significant with respect
to the rate-limiting step. The importance of C-H cleavage in the
rate-determining step further suggested that the C-H bond cleavage
a
Reaction conditions: polyfluoroarene (0.2 mmol), benzene (0.8 mL),
Pd(OAc)
2
(10 mol %), Cu(OAc)
2
(2 equiv), Na
2
CO
3
(0.75 equiv), PivOH
(20 mol %).
b
(
1.5 equiv), DMA (2 mL), 110 °C, 24 h. Pd(OAc)
2
was less reactive, producing the mixture of mono- and diarylation
products in 20% overall yield (see the Supporting Information).
Subsequently, we investigated the substrate scope with regard
to the simple arene (Scheme 3). Monosubstituted benzenes under-
went the reaction to generate a mixture of para and meta
regioisomers regardless of electron-donating or electron-withdraw-
ing substituents (3m-p), indicating that the electronic effects of
the substituents do not affect the regioselectivity of the reaction.
Good yields were obtained for these reactions, except in the case
of nitrobenzene, which was deactivated by the strongly electron-
withdrawing nitro group. For 1,2- or 1,3-disubstituted benzenes,
the reaction selectively occurred at the less hindered C-H site.
When two substitutents were identical, these reactions exhibited
excellent regioselectivity (3r-t). These results indicate that the
steric factors of substituents play a key role in controlling the
reactivity and regioselectivity, in agreement with the observations
by Sanford and Buchwald. It is noteworthy that in comparison
with toluene, more electron-poor simple arenes such as 1,2-
dichlorobenzene and trifluoromethylbenzene produced slightly more
homocoupling byproducts, although the amounts of these byproduct
were barely detectable.
To find out which one of the two C-H bond-cleavage processes
was involved in the rate-limiting step, we determined the values
Scheme 3. Scope of Simple Arenes in Pd(OAc)
Oxidative Arylation
2c,d,8
may proceed via a concerted metalation-deprotonation pathway,
as the typical electrophilic aromatic substitution pathway does not
1
3
involve C-H cleavage in the rate-limiting step. This hypothesis
for the pathway of C-H cleavage can account for the observations
that the reactions of electron-poor simple arenes yielded more
homocoupling byproducts than those of benzene and toluene.
In summary, we have developed an efficient and straightforward
method for the formation of aryl-aryl bonds via Pd(OAc) -mediated
2
dual C-H bond activation. This approach represents a promising
1
4
2c,g,h,p
alternative to the existing C-M/C-X and C-H/C-X
coupling methods for producing fluorinated biaryls. The establish-
ment of cross-coupling of two electronically different arenes should
influence the design of new cross-coupling reactions. Our ongoing
work is devoted to expanding the C-H/C-H cross-coupling
reaction to a broad spectrum of substrates.
5
b
5d
Acknowledgment. Financial support from the 973 Program
(
“
2006CB932903, 2009CB939803), NSFC (20821061, 20925102),
The Distinguished Oversea Scholar Project”, “One Hundred Talent
2
-Catalyzed
a
Project”, the Knowledge Innovation Program of CAS, and the Key
Project from CAS is greatly appreciated.
Supporting Information Available: Detailed experimental proce-
dures and characterization of products. This material is available free
of charge via the Internet at http://pubs.acs.org.
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J. AM. CHEM. SOC. 9 VOL. 132, NO. 46, 2010 16379