Angewandte
Chemie
DOI: 10.1002/anie.200703002
Cascade Reactions
Cascade Reactions Using LiAlH4 and Grignard Reagents in the
Presence of Water**
M. Brett Runge, Martin T. Mwangi, A. Lee Miller II, Mathew Perring, and Ned B. Bowden*
The development of cascade reactions—often called domino,
tandem, or multicomponent reactions—is a major challenge
in chemistry because of the difficulties in carrying out
multiple reactions in one vessel.[1–4] These reactions are
attractive goals because they save time and materials while
producing less waste than the tradition method of carrying out
reactions one at a time followed by purification and charac-
terization of each product. In cascade reactions, two or more
reactions are carried out in one reaction vessel so the number
of purification and characterization steps are lowered which
speeds up the synthesis. These reactions have the potential to
change how molecules are synthesized in academic and
industrial laboratories. For example, the synthesis of one
kilogram of a pharmaceutical product typically yields 25 to
100 kilograms of waste; this amount of waste could be
lowered through the use of cascade reactions.[3,5] Most
methods to carry out cascade reactions use one catalyst that
is responsible for catalyzing two or more reactions. Although
highly successful when discovered, these reactions fail to use
many of the catalysts and reagents that have been reported
that are successful for one reaction but are not readily
integrated into cascade sequences. An important frontier in
this field is to develop methods to use multiple, commercially
available catalysts or reagents in cascade reactions to increase
the complexity of products that can be produced.
challenges and limitations because it often requires additional
synthetic steps and changes both the structure and activity of
catalysts or reagents. In addition, the site-isolation of many
reagents is challenging because all or part of their structures
are integrated into the final product, thus affecting their
structures to bond them to a support alters the final product.
In addition, many reagents, such as water, LiAlH4, and
Grignard reagents, are commonly found in organic chemistry
and are inexpensive, but they are not easily site-isolated. For
instance, water and LiAlH4 rapidly react with one another
and can not be added to the same reaction vessel. Herein we
will describe a general method to site-isolate water from
LiAlH4, Grignard, or cuprate reagents to carry out a series of
cascade reactions using these reagents.
Our method for site-isolation of water from LiAlH4 and
Grignard reagents uses polydimethylsiloxane (PDMS) thim-
bles to completely encapsulate water (Figure 1). PDMS is a
The key problem with cascade reactions that use multiple
catalysts or reagents is that these components often poison
each other. A solution to this problem is to site-isolate
catalysts and reagents from each other such that they do not
come into contact and poison one another. Site-isolation is
typically carried out by bonding a catalyst to a polymer
support, a heterogeneous surface, or encapsulating it within a
sol–gel or zeolite.[2,4,6] For instance, in recent work Hawker,
FrØchet, and co-workers attached acidic and basic residues to
the interior of star polymers such that they did not quench
each other, which allowed both acid-and basec-atalyzed
reactions in the same reaction vessel.[4] Site-isolation has
Figure 1. Hexanes and small, non-ionic organic molecules have high
flux rates through PDMS (gray bar), but water has a low flux rate and
has little tendency to cross the PDMS barrier.
commercially available polymer that is very hydrophobic and
has a low glass-transition temperature which leads to it being
rubbery. PDMS is used as a membrane in separation devices
because small molecules can diffuse through it readily; in fact,
most small molecules have rates of diffusion and flux rates
through PDMS that are within an order of magnitude of each
other.[7] The flux rate is a measure of the moles of a molecule
that pass through a slab of a material per unit time and
describes whether the material allows large or small amounts
of molecules to penetrate it on reasonable time scales.
Although the flux rates of non-ionic organic molecules
through PDMS are typically high, very polar molecules and
water have low flux rates owing to their low solubilities in
PDMS. In fact, other groups have shown that ionic molecules,
such as ionic liquids, do not diffuse through PDMS because of
their low solubility in the hydrophobic matrix of PDMS.[8]
Water has a very low flux rate through PDMS owing to its
[*] M. B. Runge, M. T. Mwangi, A. L. Miller II, M. Perring,
Prof. N. B. Bowden
University of Iowa
Department of Chemistry
Iowa City, IA 52242 (USA)
Fax: (+1)319-335-1270
E-mail: ned-bowden@uiowa.edu
[**] We thank the Roy J. Carver Charitable Trust and the Research
Corporation for generous financial support. We thank the reviewers
for their suggestions that improved this article.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2008, 47, 935 –939
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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