Li’s reported method for the preparation of pyridine-
3-boronic acid (2) involves the low-temperature lithium-
halogen exchange of 3-bromopyridine (1) using n-butyl-
lithium followed by an in situ quench of the lithio species
with triisopropylborate.4 Hydrolysis of the boronate ad-
duct with aqueous acid provides the free boronic acid 2.
To isolate and purify the reagent, the authors chose to
heat a mixture of 2 in acetonitrile, resulting in the
formation of the stable 3-pyridylboroxin (3), a dehydrated
trimer (Scheme 1). The authors then converted boroxin
3 to the corresponding pinacol ester, which was fully
characterized. Boroxin 3 itself is a bench-stable com-
pound that can be easily hydrolyzed6 to provide pure
boronic acid 2 prior to subjection to the Suzuki cross-
coupling conditions. In our hands, this protocol worked
quite well to provide 3 in good yield (90% over three
steps) and was amenable to multigram-scale preparation
of our desired biphenyl target. The boroxin was substan-
tially more pure than the boronic acid adduct (>95%
Gen er a tion of 3-P yr id yl Bia r yl System s via
P a lla d iu m -Ca ta lyzed Su zu k i
Cr oss-Cou p lin gs of Ar yl Ha lid es w ith
3-P yr id ylbor oxin
Christopher L. Cioffi,* William T. Spencer,
J ustin J . Richards,† and R. J ason Herr
Medicinal Chemistry Department,
Albany Molecular Research, Inc., P.O. Box 15098,
Albany, New York, 12212-5098
chris.cioffi@albmolecular.com
Received May 16, 2003
Abstr a ct: The synthesis of 3-pyridyl biaryl systems can be
readily achieved by means of palladium-catalyzed Suzuki
cross-coupling reactions between aryl halides and 3-pyridyl-
boroxin. A series of cross-couplings were conducted in order
to investigate the scope and limitations of this protocol.
1
versus ∼85% by H and 13C NMR analyses) due to the
crystallization of 3 from acetonitrile after the trimer
formation. We have observed that 3 can be stored on the
benchtop for more than two months without any detect-
The palladium-catalyzed Suzuki cross-coupling reac-
tion between boronic acids/esters and aryl halides is a
powerful carbon-carbon bond-forming tool in organic
synthesis and is widely used in the construction of biaryl
systems.1 In our laboratories, we sought to utilize this
reaction for the preparation of a key heterobiaryl scaffold
that contained a 3-pyridyl connectivity by a cross-
coupling reaction between pyridine-3-boronic acid (2)2-4
and a proprietary aryl halide. The scale of our prepara-
tion required multigram amounts of the boronic acid 2,
but due to the high cost (∼$100/g) of 2 (and the scarce
commercial availability of the pinacol ester surrogate),
we sought to prepare it ourselves following the procedure
recently reported by Li and co-workers3,4 using the
relatively inexpensive reagent 3-bromopyridine (∼$1/g).
We were also hoping that our application to large-scale
preparation of the simple reagent 3 would also circum-
vent the use of the reagent diethyl(3-pyridyl)borane5
which, although less expensive than 2 (∼$10/g), was
limited to smaller amounts commercially available.
1
able decomposition (analysis by H NMR and LC MS).
In our experience, this method constituted a vast im-
provement over the previously reported methods for
generating 2.7
It is not as well-known that some boroxins can serve
as boronic acid surrogates for Suzuki cross-coupling
reactions.8 Although the use of aryl boroxins is well
documented in the literature,9 their primary application
has been a means by which boronic acids can be purified
and characterized.10 With 3 in hand, we decided to try
to use it as is in our cross-coupling reaction instead of
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† Undergraduate Summer Research Intern, Summer 2002.
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10.1021/jo034664d CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/14/2004
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