ROMPgel-Supported Triphenylphosphine with Potential Application in Parallel Synthesis

Article abstract of DOI:10.1021/ol026008q

(Equation Presented) ROMPgel-supported triphenylphosphine was synthesized in three steps (67%) from norbornadiene, 4-bromoiodobenzene, and chlorodiphenylphosphine. The supported reagent has a high loading (2.5 mmol/g) and favorable swelling properties in organic solvents. It has been utilized for the conversion of alcohols to halides, the reduction of ozonides, and the isomerization of α,β-acetylenic esters and in the Staudinger reaction. In general, filtration of the resin from the reaction mixtures and evaporation gave the corresponding products in high yield and purity.

Full text of DOI:10.1021/ol026008q

ORGANIC
LETTERS
2002
Vol. 4, No. 11
1975-1977
ROMPgel-Supported Triphenylphosphine
with Potential Application in Parallel
Synthesis
Erik A° rstad, Anthony G. M. Barrett,* Brian T. Hopkins, and Johannes Ko1bberling
Department of Chemistry, Imperial College of Science, Technology and Medicine,
London SW7 2AY, United Kingdom
agmb@ic.ac.uk
Received April 12, 2002
ABSTRACT
ROMPgel-supported triphenylphosphine was synthesized in three steps (67%) from norbornadiene, 4-bromoiodobenzene, and chlorodiphenyl-
phosphine. The supported reagent has a high loading (2.5 mmol/g) and favorable swelling properties in organic solvents. It has been utilized
for the conversion of alcohols to halides, the reduction of ozonides, and the isomerization of r,â-acetylenic esters and in the Staudinger
reaction. In general, filtration of the resin from the reaction mixtures and evaporation gave the corresponding products in high yield and
purity.
Immobilized reagents, catalysts, and scavenger reagents
combine the advantages of simple purification, in that only
filtration and washing are required to remove large excesses
of reagents, with the ease of reaction monitoring associated
with classical solution phase methodologies. It is therefore
not surprising that the use of solid-supported reagents has
become the subject of considerable emphasis within the past
few years. A range of such reagents has been developed, of
which most are either based on polystyrene beads or
inorganic supports.1 Recent efforts have improved their
loading and physical properties, resulting in highly versatile
reagents. Nonetheless, there is need to simplify the elabora-
tion and costs of solid-supported reagents and to further
improve their properties. In these terms, the use of polymers
derived from ring-opening metathesis (ROM) has the ad-
vantage that ruthenium carbenes can convert readily available
and highly functionalized monomers to well-defined sup-
ported reagents (ROMPgels).2 The resulting polymers have
high loadings and undergo significant swelling in various
solvents. A range of ROMPgel-supported reagents have been
prepared and used in parallel synthesis.3
Due to the many transformations involving triphenylphos-
phine and the difficulties encountered in subsequent workup,
this reagent was among the first to be made available on a
polymer support.4 To further explore the scope of the ROMP
methodology, we herein report the synthesis and utilization
of ROMPgel-supported triphenylphosphine 4.
4-Bromoiodobenzene (1) was coupled to norbornadiene
via a palladium-catalyzed exo-hydroarylation reaction to
afford the bromide 2 (80%). Bromide 2 was allowed to react
with butyllithium and chlorodiphenylphosphine to produce
the phosphine monomer 3 in 92% yield (Scheme 1).
(2) (a) Buchmeiser, M. R. Chem. ReV. 2000, 100, 1565. (b) Bielawski,
C. W.; Grubbs, R. H. Angew. Chem., Int. Ed. 2000, 39, 2903.
(3) (a) Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S.; Zecri, F. J. Org.
Lett. 1999, 1, 579. (b) Barrett, A. G. M.; Cramp, S. M.; Hennessy, A. J.;
Procopiou, P. A.; Roberts, R. S. Org. Lett. 2001, 3, 271. (c) Arnauld, T.;
Barrett, A. G. M.; Seifried, R. Tetrahedron Lett. 2001, 42, 7899. (d) Arnauld,
T.; Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S.; Zecri, F. J. Org. Lett.
2000, 2, 2663.
(1) (a) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach,
A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S.
J. J. Chem. Soc., Perkin Trans. 1 2000, 23, 3815. (b) Kirschning, A.;
Monenschein, H.; Wittenberg, R. Angew. Chem., Int. Ed. 2001, 40, 651.
(4) McKinley, S. V.; Rakshys, J. W. J. Chem. Soc., Chem. Commun.
1972, 134. For a recent example of the use of this reagent, see: Lizarzaburu,
M. E.; Shuttleworth, S. J. Tetrahedron Lett. 2002, 43, 2157 and references
therein.
10.1021/ol026008q CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/08/2002

been applied to the conversion of alcohols into halides, the
reduction of ozonides, and the isomerization of R,â-acety-
lenic esters and in the Staudinger reaction.
Scheme 1a
The conversion of alcohols into halides was carried out
by heating a mixture of the substrate and ROMPgel 4 (2
equiv) in dichloromethane and carbon tetrachloride (95:5)
at reflux (Table 1). Subsequent filtration of the resin and
Table 1. Conversion of Alcohols into Halides
Attempted polymerization of alkene 3 using the ruthenium
carbene 7 was unsuccessful presumably due to competitive
inhibition of the catalytic cycle by the phosphine residue
(Scheme 2). However, addition of trifluoroacetic acid to
Scheme 2
a Yields refer to the isolated products. Purities, as judged by 1H and 13
C
NMR spectra, IR and GC-MS, were >95% in every case.
phosphine 3 counterbalances inhibition by protonation of the
residues. Polymerization of the resultant trifluoroacetate salt
derived from phosphine 3 in the presence of the cross linker
55 (15 mol %) and neutralization gave the ROMPgel 4 (87%).
The most appealing approach to ROMPgel 4 is to use the
ruthenium catalyst 6, which provides the polymer 4 without
the need for the acidification and neutralization steps. The
reason for this is the lower affinity of the ruthenium catalyst
6 for triphenylphosphine, caused by its electron rich hetero-
cyclic carbene ligand. When a solution of monomer 3, cross
linker 5 (15 mol %), and catalyst 6 (0.5-1-mol %) in
dichloromethane was heated to 40 °C for 1 h, an insoluble
polymer was obtained in 91% yield (Scheme 1). After
termination of the polymerization with ethyl vinyl ether, the
polymer was ground up, filtered, washed repeatedly with
THF and diethyl ether, and dried. The resulting ROMPgel 4
has a high loading (2.5 mmol/g) and good swelling properties
in dichloromethane, THF, and toluene. It has successfully
washing with THF and diethyl ether afforded the corre-
sponding chlorides in excellent yields (89-100%) and high
levels of purity (>95%). It was found that the reaction time
could be reduced dramatically be heating the reaction mixture
in a microwave oven. In a similar fashion, using either carbon
tetrabromide (1.5 equiv) or I2 (1.8 equiv) as the halogen
source, bromides and iodides were produced albeit in slightly
lower yields. Prior to workup, excess carbon tetrabromide
was converted to bromoform (bp760 150 °C) by the addition
of methanol.
Triphenylphosphine is a valuable reagent for the reduction
of ozonides, but removal of triphenylphosphine oxide from
the products usually requires chromatography. In contrast,
the use of ROMPgel 4 greatly simplifies the purification.
Three ozonides were prepared by bubbling ozone through a
solution of the parent alkene in dichloromethane and 2-pro-
panol (3:1) at -78 °C until a blue color persisted. Excess
ozone was removed by passing a stream of nitrogen through
the solution when reduction of the ozonides was ac-
complished by adding ROMPgel 4 (1.5 equiv) to the mixture
(5) Arnauld, T.; Barrett, A. G. M.; Hopkins, B. T.; Zecri, F. J.
Tetrahedron Lett. 2001, 42, 8215.
1976
Org. Lett., Vol. 4, No. 11, 2002

and shaking it at ambient temperature for 2 h. Subsequent
filtration of the resin furnished the corresponding keto
aldehydes or ketones in 96-100% yield and >95% purity
(Table 2).
h). The reaction mixture was cooled to room temperature,
and aqueous ammonia (35%) was added.
When the evolution of gas ceased, the mixture was heated
to reflux for another 1-3 h. Subsequent filtration of the resin
afforded the amino derivatives in high yield (87-100%) and
purity (90-98%) (Table 3).
Table 2. Reduction of Ozonides
Table 3. Conversion of Azides to Amines
a Yields refer to the isolated products. Purities, as judged by 1H and 13
C
NMR spectra, IR and GC-MS, were >95% in every case.
Triphenylphosphine is known to catalyze the isomerization
of R,â-acetylenic esters to produce ∆2,4-dienoates.6 The latter
are common flavor constituents and important building
blocks for complex target molecules.
This important transformation was readily carried out by
heating a mixture of ethyl 2-hexynanoate, 4 (0.4 equiv), and
acetic acid (0.5 equiv) in toluene (Scheme 3). The use of
a Yields refer to the isolated products. Purities as judged by 1H and 13
NMR spectra, IR and GC-MS.
C
Scheme 3a
In conclusion, ROMPgel-supported triphenylphosphine
shows high reactivity in various transformations, including
the conversion of alcohols to halides, the reduction of
ozonides, the isomerization of R,â-acetylenic esters to
∆2,4-dienoates, and in the Staudinger reaction. The reagent
is easy to handle and, as opposed to the polystyrene based
reagent, it is straightforward to synthesize without the use
of specialized equipment or in depth knowledge of polymer
synthesis.
a Reagents and conditions: 0.4 equiv of 4, 0.5 equiv of AcOH,
PhMe, 110 °C, 18 h, 97% (90% purity).
supported phosphine in this reaction is particularly attractive
as the reagent can be recovered simply by filtration and
reused.
Finally, ROMPgel-supported triphenylphosphine has been
employed in the Staudinger reaction.7 Typically, a mixture
of the azide, 4 (2 equiv), and THF was heated to reflux until
the substrate no longer could be detected in solution (2-5
Acknowledgment. We thank Merck KGaA (to B.T.H.),
the E.U. for a Marie Curie fellowship (to J.K.), the
Norwegian Research Council (to E.A° .), and the EPSRC for
their generous support for our research. We also thank
GlaxoSmithKline for their endowment (to A.G.M.B.) and
the Wolfson Foundation for establishing the Wolfson Centre
for Organic Chemistry in Medical Science at Imperial
College.
(6) Trost, B. M.; Kazmaier, U. J. Am. Chem. Soc. 1992, 114, 7933.
(7) (a) Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F. Tetrahedron
1981, 37, 437. (b) Vaultier, M.; Knouzi, N.; Carrie, R. Tetrahedron Lett.
1983, 24, 763.
OL026008Q
Org. Lett., Vol. 4, No. 11, 2002
1977