sions of proline, creating additional incentives for the
development of these solid-supported organocatalysts. In
addition, these cross-linked beads have higher catalyst
loadings and are of a much more practical nature than the
earlier soluble polymers. Recently, Gruttadauria also intro-
duced the more powerful immobilized prolineamide catalysts
Scheme 1
.
Synthesis of Acrylic Building Blocks
4
using the same methodology.
Given the excellent catalytic performance of such polymer
solid-supported catalysts, new, more versatile, and affordable
procedures for the preparation of such polymer beads that
are useful for work on a preparative scale is of great interest.
The traditional Merrifield approach, in which catalysts are
simply anchored onto prefabricated solid supports by way
of modified catalyst precursors and used within solid-
supported organocatalysis, is well established but has certain
profound limitations. During a multistep sequential prepara-
tion, the difficulty of monitoring reactions on cross-linked
solid supports often requires several time-consuming and
costly elemental analyses, and final catalyst loadings are
somewhat unpredictable. Styrenic polymeric supports, now
7
5
ylmethacrylate (HEMA) and succinic anhydride, comprises
a “complete package” of both a methacrylate, linker and
in use for more than 40 years, are chemically very robust
but have favorable swelling characteristics in a very limited
variety of solvent systems because of the hydrocarbon nature
of styrenes. More modern solid supports with better swelling
properties, such as Tentagel, JandaJel, etc., still have styrene
chemistry at their core but are very expensive. As such, the
traditional direct anchoring of modified catalysts is more
suited for high-valued substrates/catalysts used under harsh
reaction conditions, rather than the cheap organocatalysts that
are used under mild enzyme-mimetic reaction conditions.
We want to introduce a new “bottom-up” approach for
solid-supported proline-derived organocatalysts, modular at
the monomeric rather than the polymeric level, and founded
on acrylic chemistry. Acrylic polymer chemistry spans
everything from superabsorbent acrylate “Super Slurpers”
to DuPont’s exceptionally hydrophobic fluorinated Zonyl
monomers, giving numerous possibilities for matching a
preferred set of reaction conditions. The advent of organo-
catalysis means acrylic solid supports should be especially
useful.
functional handle. It is cleanly converted to the acyl halide
7
by simple stirring in oxalyl chloride or neat SOCl
2
and
subsequent removal of the volatiles by evaporation in vacuo.
Next, plentiful variants of solid-supported proline deriva-
tives are now available through copolymerization. The free
8
radical (co)polymerization of unsaturated monomers is one
of the most atom-economic, selective, functionally tolerant,
and robust reactions available, tolerating free carboxylic
acids, alcohols, most amines, water, and low degrees of
chemical purities. Actually, it can, by analogy, be considered
a click reaction, considering the fact that the thiol-ene click
coupling is essentially a fully chain transferred free radical
9
polymerization. Both the traditional Huisgen-type azide/
alkyne cycloaddition and the thiol-ene coupling are click
reactions that Peric a` s and Gruttadauria have used in the
traditional postmodification approach to solid-supported
2
g,i-m
proline derivatives.
In our acrylic approach, such a
versatile reaction completes both the solid support and the
anchoring of the catalyst in the same step.
In our method, we have first introduced a new family of
proline (meth)acrylates 1-3 (Scheme 1). These are prepared
on large scale (10-40 g) in a one-step, non-chromatographic,
and protecting-group-free procedure directly from inexpen-
Two high-load linear polymers (4 and 5) were directly
accessed by polymerization of 1 or 2, respectively, in water
with azobis(isobutyramidine) dihydrochloride (AIBA), a
6
6
water-soluble azo-initiator (Scheme 2).
sive trans-4-hydroxy-L-proline, using methodology devel-
6
These linear polymers are brittle and glassy materials (see
Supporting Information for pictures). They present the
highest loaded form of polymer-immobilized proline avail-
able but have limited solubilities. They are soluble in
formamide, or in water in their cationic/anionic forms. These
solvents gave poor results in aldol test reactions.
We then prepared traditional polymer beads, analogues
to the traditional Merrifield resin, by suspension (droplet)
copolymerization of proline methacrylates 2 and 3 with
oped recently in our group. This circumvents the cumber-
some double Boc/Cbz protection of hydroxyproline under
6
alkaline acylations.
Acrylate 1 and methacrylate 2 are prepared from acryloyl
and methacryloyl chloride, respectively, while methacrylate
3
is prepared from commercially available 2-methacryloyl-
oxyethylsuccinic acid. This latter, inexpensive, and conve-
nient methacrylate, derived from the industrial hydroxyeth-
(
4) Gruttadauria, M.; Giacalone, F.; Marculescu, A. M.; Noto, R. AdV.
Synth. Catal. 2008, 350, 1397.
5) (a) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149. (b) Merrifield,
R. B. Science 1965, 150, 178.
6) Kristensen, T. E.; Hansen, F. K.; Hansen, T. Eur. J. Org. Chem.
009, 387.
(7) van Esch, J.; Schoonbeek, F.; de Loos, M.; Kooijman, H.; Spek,
A. L.; Kellogg, R. M.; Feringa, B. L. Chem.sEur. J. 1999, 5, 937.
(8) Moad, G.; Solomon, D. H. The Chemistry of Radical Polymerization,
2nd ed.; Elsevier: Amsterdam, Boston, 2006.
(
(
2
(9) Dondoni, A. Angew. Chem., Int. Ed. 2008, 47, 8995.
Org. Lett., Vol. 11, No. 14, 2009
2969
Kristensen, Tor E.
