Free radical reactions on soluble supports from ring-opening metathesis

Article abstract of DOI:10.1021/ol016632n

Equation presented Free radical reactions were performed on soluble ring-opening metathesis (ROM) polymers. These polymers have high substrate loading, short reaction times, and the benefit of a facile purification. All reactions on these supports were obtained in good yields as white crystalline-like materials readily separated from tin byproducts.

Full text of DOI:10.1021/ol016632n

ORGANIC
LETTERS
2001
Vol. 3, No. 21
3397-3399
Free Radical Reactions on Soluble
Supports from Ring-Opening Metathesis
Eric J. Enholm* and Maria E. Gallagher
Department of Chemistry, UniVersity of Florida, GainesVille, Florida 32611
enholm@chem.ufl.edu
Received August 22, 2001
ABSTRACT
Free radical reactions were performed on soluble ring-opening metathesis (ROM) polymers. These polymers have high substrate loading,
short reaction times, and the benefit of a facile purification. All reactions on these supports were obtained in good yields as white crystalline-
like materials readily separated from tin byproducts.
Recent interest in soluble organic supports has demonstrated
that these polymers can be applied to a variety of standard
synthetic transformations and offer significant advantages
over popular classic hard resin supports.1 Unlike standard
solid-phase organic synthesis, huge excesses and/or concen-
trated reagents are not necessary because soluble support
offers the faster reaction kinetics of a single solution phase.
These supports, soluble in chloroform, THF, ether, hexanes,
and CH2Cl2, can also be conveniently monitored by standard
1H NMR spectroscopy without cleavage from the polymer
backbone.
phase resins cannot achieve this level of loading mainly
because the substrate is incompletely covalently attached to
the polymer. With this methodology, the substrate is
completely incorporated into each monomer and then
subsequently polymerized.
We decided to use norbornyl monomers in these studies
for three reasons.3 First, they polymerize readily by ring-
opening metathesis with Grubbs well-defined ruthenium
catalysts.4 The small amount of strain inherent with nor-
bornenes assists and accelerates the metathesis.5 Second, a
wide variety of norbornenes are commercially available or
Since most soluble supports are not readily available
commercially, we have prepared them by custom synthesis
for each particular application as “designer supports”. We
now report a soluble designer support compatible with free
radical transformations made from ring-opening metathesis
polymerizations. Prior to our work, soluble organic supports
were not applied to radical reactions.2
Each monomer unit contains one or two reaction sites
integrated into the backbone so that the designer polymer
essentially has 100-200% loading capacity. Standard solid-
(2) For recent examples of radical reactions on solid-phase resins, see:
(a) Yim, A.-M.; Vidal, Y.; Viallefont, P.; Martinez, J. Tetrahedron Lett.
1999, 40, 4535. (b) Caddick, S.; Hamza, D.; Wadman, S. N. Tetrahedron
Lett. 1999, 40, 7285. (c) Zhu, X.; Ganesan, A. J. Comb. Chem. 1999, 1,
157. (d) Sibi, M. P.; Chandramouli, S. V. Tetrahedron Lett. 1997, 8929-
8932.
(3) For examples of ROMP supports in synthesis, see: (a) Ball, C. P.;
Barrett, A. G. M.; Poitout, L. F.; Smith, M. L.; Thorn, Z. E. Chem. Commun.
1998, 2453-2454. (b) Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S.;
Zecri, F. J. Org. Lett. 1999, 1, 579-582. (c) Barrett, A. G. M.; Cramp, S.
M.; Roberts, R. S.; Zecri, F. J. Org. Lett. 2000, 2, 261-264. (d) Arnauld,
T, Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S.; Zecri, F. J. Org. Lett.
2000, 2, 2663-2666.
(4) (a) Maughon, B. R.; Grubbs, R. H. Macromolecules 1997, 30, 3459-
3469. (b) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 2000,
1, 953-956. Chang, S.; Jones, L.; Wang, C. M.; Henling, L. M.; Grubbs,
R. H. Organometallics 1998, 17, 3460-3465.
(5) Makovetsky, K. L.; Finkelshtein, E. S.; Ostrovskaya, I. Y.; Portnykh,
E. B.; Gorbacheva, L. I.; Goldberg, A. L.; Ushakov, N. V.; Yampolsky, Y.
P. J. Mol. Catal. 1992, 76, 107-121.
(1) (a) Wentworth, P.; Janda, K. D. Chem. Commun. 1999, 1917-1924.
(b) Toy, P. H.; Janda, K. D. Tetrahedron Lett. 1999, 40, 6329-6332. (c)
Gravert, D. J.; Janda, K. D. Curr. Opin. Chem. Biol. 1997, 1, 107-113.
(d) Enholm, E. J.; Gallagher, M. E.; Lombardi, J. S.; Moran, K. M.; Schulte,
J. P. Org. Lett. 1999, 1, 689-691. (e) Enholm, E. J.; Schulte, J. P. Org.
Lett. 1999, 1, 1277-1279.
10.1021/ol016632n CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/15/2001

readily prepared by by Diels-Alder reactions. Third, they
are easily substituted with halides and other radical precur-
sors. The supports we use contain alkenes, but these are
“protected” from radical reactions by the bulk of the polymer
backbone as these yields readily demonstrate. The overall
radical reaction process is illustrated in Scheme 1. In this
polymer with excess ethyl vinyl ether.7 The reaction mixture
was then slowly poured into methanol with brisk agitatation,
producing a polymer filtered as a white solid precipitate. A
longer reaction time resulted in the formation of an undesir-
able insoluble gel. Termination of the polymerization early
in the reaction limits the molecular weights of the polymers,
thereby allowing for complete solubility in organic solvents.
Monitoring the polymerization reactions was conveniently
1
done through the use of H NMR spectroscopy.
Scheme 1
Both R-bromo ROM polymers 5a and 5b were treated with
allyltributyltin under free radical conditions at reflux to afford
the corresponding allylated products 6a and 6b on designer
support (Scheme 3). Cleavage of the allylated esters and
Scheme 3
reaction, our designer ROMP support 1 tethers a bromoester
on a cyclopentane ring that forms part of the backbone of
the polymer. Replacement of the halogen by one of two free
radical processes allows for the introduction of an allyl unit
in a carbon-carbon bond-forming process or a hydrogen
atom in a reductive reaction. In this reaction, a tributyltin
moiety bears the transferred group that replaces the bromide
in a free radical chain process.6 By saponication, recovery
of the polymer backbone and isolation of a new carboxylic
acid should also be possible, demonstrating both the feas-
ability of cleavage of the substrate and the possible reusability
of the support.
recovery of the support was completed through lithium
hydroxide saponification, affording acids 7a and 7b in 87%
and 76% yields, respectively.
Construction of the soluble support is shown in Scheme
2. Norbornene-1-carboxaldehyde (2) was reduced to 2-nor-
Reductive reactions by hydrogen atom transfer are shown
in Scheme 4. Thus, supported bromoesters 5a and 5b were
Scheme 2
Scheme 4
bornenemethanol (3). Esterification of 2-bromopropioic acid
or 2-bromo-2-phenylacetic acid with DCC gave compounds
4a and 4b, respectively, which were then polymerized with
Grubbs catalyst to prepare 5a and 5b. The polymerization
of each norbornene was halted in 25 s by capping the
also reduced with tributyltin hydride under free radical
conditions, giving dehalogenated esters 8a and 8b, respec-
tively. Ester 8a was saponified and acidified to propionic
acid (9a), which was identical to an authentic sample.
Scheme 5 shows our efforts to increase the number of
reactive sites for each monomer unit. Two functional groups
per unit would double the loading capacity of this polymer
(6) For reviews of radical reactions, see: (a) Giese, B. Radicals in
Organic Synthesis: Formation of Carbon-Carbon Bonds; Pergammon
Press: New York, 1986. (b) Curran, D. P. Synthesis 1988, 417, 489. (c)
Motherwell, W. B.; Crich, D. Free Radical Chain Reactions in Organic
Synthesis; Academic Press: New York, 1992.
(7) Gordon, E. J.; Gestwicki, J. E. Strong, L. E.; Kiessling, L. L. Chem.
Biol. 2000, 7, 9-16.
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Org. Lett., Vol. 3, No. 21, 2001

Scheme 5
Scheme 6
support. Norbornene-2,3-dicarboxylic anhydride (10) was
reduced with lithium aluminum hydride to afford 5,6-
bishydroxymethylnorborn-2-ene (11). Coupling with 2-bromo-
2-phenylacetic acid gave the norbornene diester 12 in good
yield.
Scheme 6 shows the polymerization of 12 using Grubbs
catalyst followed by capping with ethyl vinyl ether to produce
polymer 13 in 79% yield, setting the stage for subsequent
radical reactions on both appendages. In net effect, this
polymer is highly efficient, giving more than double the
output of most standard solid-phase resins per monomer unit.
Upon treatment with allyltributyltin, under standard free
radical conditions, both bromides were replaced with new
carbon-carbon bonds, introducing two allyl units in 14a in
a 76% isolated yield as a white crystalline-like powder from
cold methanol. A similar treatment of 14 with tributyltin
hydride replaced the bromides with hydrogen atoms and
constructed 14b in 77% yield. Recovery of the polymers and
the acids 7b and 15b was easily achieved with LiOH in
saponification reactions in good yields.
phase chemistry. The reaction rates on these designer
supports are essentially the same as those for traditional
solution-phase radical reactions, and tin pollution is virtually
eliminated. To the best of our knowledge, this is the first
example of a free radical reaction performed on a soluble
polymer derived from a ring-opening metathesis polymeri-
zation. Efforts are currently directed to applying this support
to other free radical processes.
Acknowledgment. We gratefully acknowledge support
by the National Science Foundation (Grant CHE-0111210)
for this work.
Supporting Information Available: Spectral information
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
In summary, radical reactions on soluble polymers derived
from ring-opening methathesis provide high substrate loading
and facile purification and offer the ease of 100% solution-
OL016632N
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