Angewandte
Chemie
DOI: 10.1002/anie.200906710
Synthetic Methods
Multistep Phase-Switch Synthesis by Using Liquid–Liquid Partitioning
of Boronic Acids: Productive Tags with an Expanded Repertoire of
Compatible Reactions**
Sam Mothana, Jean-Marie Grassot, and Dennis G. Hall*
In memory of Keith Fagnou (1971–2009)
There are increasing environmental pressures to improve the
sustainability of reaction processes in synthetic organic
chemistry. In response to these demands, new techniques
and strategies are needed to accelerate and facilitate the
synthesis and isolation of organic compounds while minimiz-
ing the consumption of solvents and chromatographic sup-
ports that contribute to the waste stream. Indeed, much of the
wastes produced in organic reactions originate from the
extensive use of silica gel and solvents employed in chromato-
graphic purification steps. Phase-switching strategies are very
attractive as a means to avoid chromatography.[1] In phase-
switch chemistry, reactions take place conveniently under
homogeneous conditions, and product separation is facilitated
by a liquid–liquid partition or a precipitation/filtration
operation. Phase trafficking is possible through functionaliz-
ing the substrate or reagents with a phase “tag”. Several
ingenious phase-switching strategies were developed and
employ various tags such as perfluoroalkyl groups,[2] polyeth-
ylene glycol chains,[3] metal chelators,[4] H-bonding recep-
tors,[5] polymerizable norbornene groups,[6] polyaromatics,[7]
phosphonium salts,[8] and others.[9] Whereas many of these
strategies have been used for tagging reagents or catalysts,
only a few were employed for tagging substrates and even
fewer allowed for multistep syntheses to be implemented. In
all of these methods, however, the requirement for a phase tag
creates two chemically unproductive steps: attachment of the
tag to the substrate, and detagging of the product at the end.
The latter operation destroys the phase tag and often leaves
an undesired remnant (or “trace”) on the desired product.
Recently, we have introduced a less invasive phase-switching
strategy involving the boronic acid functionality as a built-in,
productively convertible phase tag (Scheme 1).[10] Rather
than cleaving the extraneous tag at the end of a synthetic
Scheme 1. Concept of phase-switch synthesis using boronic acids as
productive tags.
sequence, as in other phase-switch systems, the boronic acid
can be derivatized productively using the wide range of
selective transformations known for this class of com-
pounds.[11] Owing to the commercial availability of hundreds
of functionalized boronic acids, which can serve as potential
substrates in many synthetic applications, this atom-econom-
ical phase-switch system can also circumvent the tag-attach-
ment step. Moreover, as boronic acids react only under
specific conditions (e.g., transition-metal activation),[11] their
use as inert tags should be compatible with a wide range of
chemical transformations.
Our first-generation system employed the diethanolami-
nomethyl polystyrene (DEAM-PS) resin[12] to phase-switch
boronic acids through solid-phase immobilization.[10]
Although this system proved suitable, the use of a solid
support requires extensive solvent washes after each immo-
bilization operation, and the scalability is limited compared to
strategies based on liquid–liquid partitioning. We envisioned
the development of a liquid–liquid, water–organic phase-
switching system that would exploit the known ability of
boronic acids to form strong water-soluble complexes with
polyols at high pH (Scheme 2).[13] For this application, we
sought a polyol additive that would be polar enough to
efficiently phase-switch hydrophobic boronic acids into an
aqueous phase. The additive should also be completely
insoluble in organic solvents so as to avoid contamination of
the organic layer. This strategy, illustrated in Scheme 2, allows
excess reagents and nonpolar side-products to be eliminated
with ease at the end of the reaction. Therefore, upon
[*] S. Mothana, Dr. J.-M. Grassot, Prof. D. G. Hall
Department of Chemistry, Gunning-Lemieux Chemistry Centre
University of Alberta, Edmonton, Alberta, T6G 2G2 (Canada)
Fax: (+1)780-492-8231
E-mail: dennis.hall@ualberta.ca
[**] Acknowledgements for financial support of this research is made to
the Donors of the ACS Petroleum Research Fund (grant AC-47575-
AC1), to the Natural Sciences and Engineering Research Council
(NSERC) of Canada (Discovery Grant to D.G.H.), and to the
University of Alberta.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2010, 49, 2883 –2887
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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