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10.1002/chem.201900921
Chemistry - A European Journal
FULL PAPERS
DOI: 10.1002/cctc.200((will be filled in by the editorial staff))
Pd/C as heterogeneous catalyst for the direct
arylation of (poly)fluorobenzenes
Shuxin Mao,[a] Xinzhe Shi,[a] Jean-François Soulé*[a] and Henri Doucet*[a]
This article is dedicated to the memory of the late Professor Keith Fagnou (1971-2009) who discovered the specific reactivity of
polyfluorobenzenes in catalyzed direct arylations and received the OMCOS award in 2009.
hydroxylation; whereas, at lower temperatures the expected
The potential of the heterogeneous catalyst 10% Pd/C in direct
pentafluorobiphenyls
were
obtained.
With
the
other
arylation of (poly)fluorobenzene derivatives was investigated. In
general, high yields in biaryl derivatives were obtained using tri-, tetra-
polyfluorobenzene derivatives, no C-F bond cleavage was observed.
These arylations were performed using only 1 mol% Pd/C catalyst
and KOAc as inexpensive base. As Pd/C catalyst can be easily
removed at the end of the reaction, as there is no contamination with
phosphine ligand residues, and as the major side-products of the
reaction are KOAc associated to HBr, this protocol represents a very
attractive access to (poly)fluoro-substituted biphenyls in terms of cost,
simplicity and sustainable chemistry.
and penta-fluorobenzenes.
Conversely, mono- and di-
fluorobenzenes exhibited a poor reactivity. The regioselectivities of
the arylations were similar to those observed using homogeneous
palladium catalysts. Both electron-withdrawing and electron-donating
substituents such as nitrile, nitro, acetyl, ester, trifluoromethyl, tbutyl,
methoxy or methyl on the aryl bromide were tolerated. Unexpectedly,
from pentafluorobenzene at 150°C, tetrafluoro-substituted [1,1'-
biphenyl]-4-ols were obtained due to
a regioselective formal
Stille, Suzuki and Negishi couplings represent very efficient
tools for the formation of a very wide variety of fluoro-substituted
biaryls, but they require the preliminary synthesis of
organometallic or boron derivatives and provide a stoichiometric
amount of metallic or boron side products.[2] In 2006, Fagnou et
al. reported the first intermolecular Pd-catalyzed arylation reaction
via a C-H bond activation[3] using polyfluorobenzene derivatives.[4]
Since these seminal results, the Pd- or Cu-catalyzed so-called
direct arylations of tri-, tetra- and especially penta-
fluorobenzenes[5-7] proved to be very powerful methods for the
one step access to a variety of polyfluoro-substituted biaryls
(Scheme 1, top).[8] However, to our knowledge, in all cases,
these reactions were performed using homogeneous catalysts.
Introduction
Many useful bioactive compounds contain
a fluoro-
substituted bi(hetero)aryl unit. For example, the 2,4-difluoro-1,1'-
biphenyl derivative Diflunisal is a non-steroidal anti-inflammatory
drug which is employed for the treatment of arthritis or dental pain
(Fig 1). Flurbiprofen is also a non-steroidal anti-inflammatory
drug employed for the treatment of miosis, and Tedizolid is an
oxazolidinone-class antibiotic.
Vorapaxar, Pitavastatin and
especially Rosuvastatin, which contain heteroaryl-substituted
fluorobenzenes, are also important drugs. In addition, polyfluoro-
substituted bi(hetero)aryl units are very important structures in
organic material science.[1] Therefore, the discovery of simple
and cost effective procedures for the access to (poly)fluoro-
substituted bi(hetero)aryls has potential for medicinal and
material chemistry.
Currently, the substrate scope of the Pd-catalyzed direct
arylation of benzene derivatives using heterogeneous catalysts is
very limited.[9] In 2006, Fagnou et al. revealed that Pd(OH)2/C
catalyst promotes the intramolecular direct arylation of a range of
aryl iodides to produce 5- and 6-membred ring heterocycles.[10]
To our knowledge, the intermolecular direct arylation of
(poly)fluorobenzene derivatives using Pd/C catalyst has not been
described yet; whereas, good results have been obtained using
heteroarenes.[11] The mechanism of such Pd/C catalyzed direct
arylations of heteroarenes was not elucidated;[12,13] but based on
the report by Conlon et al. on the Suzuki-Miyaura reaction using
Pd/C catalyst, such reactions might have a homogeneous
component due to the formation of soluble Pd-species.[12a] The
desorption of the palladium from Pd/C to produce soluble Pd(II)
species probably occurs after the oxidative addition of the aryl
halide on the Pd/C surface.
Figure 1. Examples of drugs containing a fluoro-substituted bi(hetero)aryl unit
[a]
Mr Shuxin Mao, Mrs Xinzhe Shi, Dr. Jean-François Soulé, Dr. Henri
Doucet
Univ Rennes, CNRS, ISCR-UMR 6226, F-35000 Rennes, France.
E-mail: jean-francois.soule@univ-rennes1.fr; henri.doucet@univ-
rennes1.fr
1
Supporting information for this article is given via a link at the end of the
document
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