DOI: 10.1002/asia.201101019
Cross-Coupling of Aryllithiums with Aryl and Vinyl Halides in Flow
Microreactors
Aiichiro Nagaki,[a] Yuya Moriwaki,[a] Suguru Haraki,[a] Akira Kenmoku,[b]
Naofumi Takabayashi,[a] Atsushi Hayashi,[a] and Jun-Ichi Yoshida*[a]
Abstract: The use of Pd catalysts that
contained a carbene ligand, such as
PEPPSI-SIPr, speeded up the Muraha-
shi coupling of ArLi with ArBr, by en-
abling its integration with the Br/Li ex-
change of ArBr with BuLi in flow.
Space integration realized the rapid
cross-coupling of two different ArBr
substrates. However, the cross-coupling
reaction with vinyl halides could not be
achieved under similar conditions. Pd-
AHCTUNGRTEN(GNUN OAc)2 was an effective catalyst, and
the space integration of the Br/Li ex-
change of ArBr with BuLi and the
Murahashi coupling with vinyl halides
was successfully achieved.
Keywords: arenes · cross-coupling ·
halides · lithiation · microreactors
Introduction
cross-coupling of organolithium compounds with organic
halides.[3–5] However, since then, to the best of our knowl-
edge, further studies have not been reported. One of the
major reasons for the lack of further work seems to be as
follows: The halogen/lithium (X/Li) exchange of ArX with
nBuLi, which is one of the most-powerful methods for gen-
erating ArLi compounds, leads to the formation of nBuX.
However, ArLi reacts with BuX if the subsequent coupling
step is slower, which is often the case. Typically, cross-cou-
pling reactions take hours to proceed to completion at room
temperature or above, whereas reactions of ArLi with alkyl
halides, such as nBuX, are complete within minutes at 08C.
If this problem can be avoided, the integration of X/Li ex-
change and Murahashi coupling reactions will then enable
the cross-coupling of two aryl halides, hence providing
a powerful tool in organic synthesis.[6–7] Although tBuLi
does not suffer from such a problem, the use of two equiva-
lents of highly reactive tBuLi is not suitable for large-scale
laboratory synthesis and industrial production.
Recently, we reported that X/Li exchange of ArX and
subsequent reactions with electrophiles could be conducted
in flow microreactor systems.[8–11] This finding prompted us
to study the integration[12] of the X/Li exchange and Mura-
hashi coupling reactions in a flow microreactor system.[13] In
a preliminary communication, we reported that the space in-
tegration[14] of X/Li exchange and Murahashi coupling could
be achieved by using an integrated flow microreactor system
if an appropriate catalyst was used (Scheme 1a);[15] in that
instance, Murahashi coupling was much faster than the com-
peting reactions with alkyl halides such as nBuX. More re-
cently, we also found that the cross-coupling reactions of
ArLi with vinyl halides could be achieved with an alterna-
tive catalyst. In addition, H/Li exchange was also effective
for generating ArLi species in some cases, especially hetero-
aryl compounds; therefore, the space integration of H/Li ex-
change with Murahashi coupling enabled the cross-coupling
of heteroaromatic compounds with aryl halides
The palladium-catalyzed cross-coupling reactions of aryl–
metal species with organic halides serve as a powerful
method for carbon carbon bond formation in the synthesis
À
of a variety of functional materials and biologically active
compounds.[1] Aryl–boron, –silane, –tin, –zinc, and –magne-
sium compounds are typically used for these cross-coupling
reactions because they are relatively stable. In particular,
the Suzuki–Miyaura cross-coupling reaction[2] has been used
extensively owing to the air- and moisture stability of boron-
ic acids and their derivatives. In contrast, the use of organo-
lithium compounds in cross-coupling reactions has been
rather limited, although many aryl–metal species, including
aryl–boron compounds, are readily prepared from aryllithi-
um compounds that themselves can be generated by various
methods, such as halogen/lithium exchange, deprotonation,
and sulfoxide/ or sulfone/metal exchange. Therefore, the
direct use of organolithium compounds, such as aryllithium
species for the palladium-catalyzed cross-coupling reaction,
should be considered more seriously, in particular, from the
viewpoint of atom- and step economy. In 1979, Murahashi
et al. reported a pioneering work on the palladium-catalyzed
[a] Dr. A. Nagaki, Y. Moriwaki, S. Haraki, N. Takabayashi, A. Hayashi,
Prof. Dr. J.-I. Yoshida
Department of Synthetic and Biological Chemistry
Graduate School of Engineering
Kyoto University
Nishikyo-ku, Kyoto, 615-8510 (Japan)
Fax : (+81)75-383-2727
[b] A. Kenmoku
The Research Association of Micro Chemical
Process Technology (MCPT)
Nishikyo-ku, Kyoto 615-8510 (Japan)
Supporting information for this article is available on the WWW
Chem. Asian J. 2012, 7, 1061 – 1068
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