Chinese Chemical Letters
Original article
Arylation of pyridine N-oxides via a ligand-free Suzuki reaction in
water
*
Chun Liu , Shao-Ke Zhang, Yi-Xia Zhang, Zi-Lin Jin
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
A R T I C L E I N F O
A B S T R A C T
Article history:
We report a practical and highly efficient protocol for the arylation of pyridine N-oxides with arylboronic
acid through palladium-catalyzed Suzuki reaction in water. This ligand-free Suzuki reaction is
performed in the presence of diisopropylamine and gives 2- or 3-arylated pyridyl N-oxide derivatives in
good to excellent yields within 1 h.
Received 22 May 2014
Received in revised form 14 August 2014
Accepted 4 September 2014
Available online 28 September 2014
ß 2014 Chun Liu. Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of
Materia Medica, Chinese Academy of Medical Sciences. All rights reserved.
Keywords:
Pyridine N-oxides
Arylation
Palladium
Suzuki reaction
Water
1. Introduction
powerful tools to form biaryls, which has been extensively used in
the synthesis of pharmaceuticals, herbicides, natural products and
Given the importance of pyridine N-oxide derivatives in
medical chemistry as well as their easy deoxygenation to the
more important pyridine derivatives, methods for the synthesis of
pyridine N-oxide derivatives continue to attract considerable
interest in organic synthesis [1–5]. Fagnou et al. reported the
palladium-catalyzed regioselective direct arylation of pyridine N-
oxides with aryl bromides, which was used for the preparation of
substituted pyridines and other heterocycles [6,7]. Recently, the C–
H bond activation approach using pyridine N-oxides was served as
an attractive platform for the 2-functionalization of pyridine
species [8–14]. However, these methods require harsh conditions
and long reaction time.
In 1999, Lohse et al. reported a catalytic system of DME/H2O/
K2CO3/5%Pd(PPh3)4 for the Suzuki cross-coupling reaction be-
tween 2- or 4-chloropyridine N-oxide and arylboronic acid,
affording 65%–70% isolated yield of the desired products, which
provided an alternative for the synthesis of aryl-substituted
pyridine N-oxide derivatives [15]. To the best of our knowledge,
this is the only example of the arylation of pyridine N-oxides via
the Suzuki reaction. The palladium-catalyzed Suzuki reaction of
aryl halides with arylboronic acids is one of the most versatile and
advanced functional materials [16,17]. However, N-heteroaryl
halides are generally inactive substrates for the Suzuki reaction
due to the potential coordination of the nitrogen to the active
palladium species [18]. So far, a lot of achievements have been
made to activate these substrates, including the development of
ligand-promoted protocols as Lohse et al. did [15]. Our group has
reported ligand-free approaches to activate 2-bromopyridine
derivatives successfully in ethylene glycol or EtOH/H2O
[19,20]. At the moment, we are interested in activating 2-
bromopyridine derivatives for the palladium-catalyzed Suzuki
reaction in water without any additional ligand.
Theuseofwaterassolereactionmediumhasseveraladvantages,
such as abundance, non-toxic, non-corrosiveness and improved
safety [21–25]. Developing organic reaction in pure water is one
of the latest challenges for modern chemists. Herein, we report
an efficient method for the Pd(OAc)2-catalyzed Suzuki reaction of
2- or 3-bromopyridine N-oxides in pure water without any ligand.
2. Experimental
Aryl halides and arylboronic acids were purchased from Alfa
Aesar. Other chemicals were obtained commercially and used
without purification. 1H NMR spectra were recorded on a Bruker
AvanceII 400 spectrometer using TMS as internal standard. 13C
NMR spectra were recorded at 100 MHz using TMS as internal
*
Corresponding author.
1001-8417/ß 2014 Chun Liu. Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. All rights reserved.