PS-COD and PS-9-BBN: Polymer-supported reagents for solution-phase parallel synthesis

Article abstract of DOI:10.1021/ol047458g

(Chemical Equation Presented) 1,5-Cyclooctadiene was deprotonated under LICKOR conditions and reacted with Merrifield resin to afford an immobilized cyclooctadiene in high yield. This polymer is effective as a halogen scavenger, while hydroboration leads to a supported 9-BBN analogue. The latter exhibits similar regioselectivity to 9-BBN in olefin hydroboration.

Full text of DOI:10.1021/ol047458g

ORGANIC
LETTERS
2005
Vol. 7, No. 5
831-833
PS-COD and PS-9-BBN:
Polymer-Supported Reagents for
Solution-Phase Parallel Synthesis†
Jefferson D. Revell,‡ Barbara Dorner,§ Peter D. White,§ and A. Ganesan*,‡
1
Combinatorial Centre for Excellence, School of Chemistry, UniVersity of Southampton,
Southampton SO17 1BJ, United Kingdom, and NoVabiochem, Merck Biosciences,
Weidenmattweg 4, Laufelfingen, Switzerland CH-4448
ganesan@soton.ac.uk
Received December 10, 2004
ABSTRACT
1,5-Cyclooctadiene was deprotonated under LICKOR conditions and reacted with Merrifield resin to afford an immobilized cyclooctadiene in
high yield. This polymer is effective as a halogen scavenger, while hydroboration leads to a supported 9-BBN analogue. The latter exhibits
similar regioselectivity to 9-BBN in olefin hydroboration.
Phase separation methods are central1 to the implementation
of high-throughput organic chemistry. Solid-phase synthesis
facilitates the use of large reagent excesses to drive reactions
forward, as workup is achieved by simple filtration. Nev-
ertheless, the method has other limitations, and hybrid
technologies have evolved to combine the desirable features
of solution- and solid-phase synthesis. One attractive option2
involves the immobilization of reagents or scavengers for
reaction workup, rather than the compound being made. The
Ley group in particular has devised numerous multistep
routes3 that rely solely on such processes.
reducing agents, borane was coordinated4 to a Lewis basic
polymer or immobilized with a chiral ligand5 as pioneered
by Itsuno for enantioselective reductions. Meanwhile, im-
mobilized alkylboranes are unprecedented in the literature.
Our objective was a polymer-supported version of the
reducing agent 9-borabicyclo[3.3.1]nonane (9-BBN). Due to
its ease6 of preparation, high stability in air, and exceptional
regioselectivity7 in hydroboration, 9-BBN is a popular8
(3) For example: (a) Baxendale, I. R.; Lee, A.-L.; Ley, S. V. J. Chem.
Soc., Perkin Trans. 1 2002, 1850-1857. (b) Baxendale, I. R.; Ley, S. V.;
Nessi, M.; Piutti, C. Tetrahedron 2002, 58, 6285-6304. (c) Storer, R. I.;
Takemoto, T.; Jackson, P. S.; Brown, D. S.; Baxendale, I. R.; Ley, S. V.
Chem. Eur. J. 2004, 10, 2529-2547.
Despite the many reported as well as commercially
available immobilized reagents and scavengers, significant
gaps exist in our armamentarium. For example, among
(4) Rajasree, K.; Devaky, K. S. J. Appl. Polym. Sci. 2001, 82, 593-
600.
(5) For example: (a) Itsuno, S.; Nakano, M.; Ito, K.; Hirao, A.; Owa,
M.; Kanda, N.; Nakahama, S. J. Chem. Soc., Perkin Trans. 1 1985, 2615-
2619. (b) Caze, C.; El Moualij, N.; Hodge, P.; Lock, C. J.; Ma, J. J. Chem.
Soc., Perkin Trans. 1 1995, 345-349. (c) Franot, C.; Stone, G. B.; Engeli,
P.; Spondlin, C.; Waldvogel, E. Tetrahedron: Asymmetry 1995, 6, 2755-
2766. (d) Hu, J.; Zhao, G.; Yang, G.; Ding, Z. J. Org. Chem. 2001, 66,
303-304. (e) Degni, S.; Wilen, C.-E.; Rosling, A. Tetrahedron: Asymmetry
2004, 15, 1495-1499.
† Taken in part from the Ph.D. Thesis of J. D. Revell, University of
Southampton, Southampton, UK, 2004. Portions of this work were presented
at EUROCOMBI-2, 2nd International Meeting of Combinatorial Sciences,
Copenhagen, Denmark, July 2003, and ACS Prospectives: Combinatorial
Chemistry: New Methods, New Discoveries, Leesburg, VA, Sept 2003.
‡ University of Southampton.
§ Merck Biosciences.
(1) Reviews: (a) Curran, D. P. Angew. Chem., Int. Ed. 1998, 37, 1175-
1196. (b) Tzschucke, C. C.; Markert, C.; Bannwarth, W.; Roller, S.; Hebel,
A.; Haag, R. Angew. Chem., Int. Ed. 2002, 41, 3964-4000.
(2) Reviews: (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, 3815-4195. (b) Bhalay,
G.; Dunstan, A.; Glen, A. Synlett 2000, 1846-1859. (c) Hodge, P. Curr.
Opin. Chem. Biol. 2003, 7, 362-373.
(6) (a) Knights, E. F.; Brown. H. C. J. Am. Chem. Soc. 1968, 90, 5281-
5283. (b) Soderquist, J. A.; Brown, H. C. J. Org. Chem. 1981, 46, 4599-
4600.
(7) (a) Scouten, C. G.; Brown, H. C. J. Org. Chem. 1973, 38, 4092-
4094. (b) Brown, H. C.; Scouten, C. G.; Liotta, R. J. Am. Chem. Soc. 1979,
101, 96-99.
(8) Reviews: (a) Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents;
Academic Press: London, 1988. (b) Stentiford, R. A. Synlett 2000, 159.
10.1021/ol047458g CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/04/2005

reducing agent as well as a precursor to other synthetically
useful boron reagents.
by high-loading Merrifield chloromethyl polystyrene resin
(Novabiochem, 4.55 mmol/g by chloride microanalysis,
Scheme 2). After alkylation, a significant increase in mass
9-BBN is synthesized by the hydroboration of 1,5-
cyclooctadiene. For immobilization, a means for attaching
1,5-cyclooctadiene to polystyrene resins needs to be devel-
oped. Recently, we have shown9 that the anion generated
by deprotonation of 1,5-cyclooctadiene under “LICKOR”
(BuLi/KOt-Bu) superbase conditions is cleanly alkylated at
the allylic position. Thus, reaction with ethylene oxide
yielded9 hydroxyethyl cyclooctadiene 1 (Scheme 1). Conver-
Scheme 2. Synthesis of PS-COD and PS-9-BBN
Scheme 1. Solution-Phase Models for Immobilized 9-BBN
was noted for the dried resin. On the basis of residual
chloride microanalysis (0.45 mmol/g), resin 5 (PS-COD) has
a loading of 3.85 mmol/g. Hydroboration of 5 afforded PS-
9-BBN 6, with a loading of 3.24 mmol/g by boron mi-
croanalysis. Gel-phase 11B NMR of 6 shows two peaks at δ
28.0 and 19.8 ppm relative to BF3‚OEt2. The smaller peak
at 28.0 is similar to that of commercially available 9-BBN,
known to exist as a dimer. We attribute the larger resin peak
to the monomeric form, dimerization presumably being
inhibited by the resin environment.
Hydroboration of limonene with resin 6 (PS-9-BBN)
resulted in an immobilized trialkylborane. Several conditions
were investigated for oxidative release to p-menth-1en-9-
ol: (i) aq H2O2 and methanolic Bu4NOH in THF (66%); (ii)
aq H2O2 and NaOH in THF (59%); (iii) Me3NO (66%); (iv)
NaBO3 in aq THF (0%). On the basis of these results, H2O2/
Bu4NOH was selected as the method of choice, and a set of
alkenes was subjected to hydroboration/oxidation by PS-9-
sion to the benzyl ether 2 provided a solution-phase model
for the attachment of 1 to chloromethyl polystyrene. Reaction
of 2 with borane gave a white solid, which, however, did
not behave as a hydroborating agent. While the reasons for
this failure are not fully understood, the presence of the
oxygen functionality in 2 is a likely complication. Instead,
1 was reduced in two steps to ethylcyclooctadiene 3, which
upon hydroboration and removal of volatile species afforded
4 as a colorless glass. This was immediately reacted with
4-vinyl-1-cyclohexene. Upon oxidative workup, the desired
4-(1-hydroxyethyl)-cyclohexene was isolated in 67% yield,
together with ethyl cyclooctanediol (91%) arising from 4.
Hydroboration of the internal olefin in 4-vinyl-1-cyclohexene
was not observed, confirming that the hydroboration was due
to a 9-BBN-like species and not adventitious borane.
Buoyed by this success, we set out to attach 1 via a non-
heteroatom linker to polystyrene. The alcohol was converted
to the corresponding bromide (PBr3, 66%), which was then
added to lithiated polystyrene resin, prepared either by the
direct deprotonation10 of polystyrene or the lithium-halogen
exchange11 of bromopolystyrene. Subsequent reaction with
BH3 presumably generated an immobilized 9-BBN analogue.
However, alkene hydroboration/oxidation using these resins
was poor (∼10%) due to poor yields in the alkylation step.
Although lithiated polystyrene reacts well with some elec-
trophiles, we are unaware of examples with unactivated alkyl
halides.
Table 1. Alkene Hydroboration-Oxidation with PS-9-BBN
These difficulties led us to explore direct alkylation of
deprotonated 1,5-cyclooctadiene (under LICKOR conditions)
a Reaction conditions: (1) PS-9-BBN, 3 equiv of alkene, THF, 40 °C,
24 h. (2) 3 equiv of Bu4NOH (1 M in MeOH), 5 equiv of aq H2O2 (35%),
THF, rt 1 h; 50 °C, 3 h. b Percentage yield of isolated product.
(9) Revell, J. D.; Ganesan, A. J. Org. Chem. 2002, 67, 6250-6252.
(10) Fyles, T. M.; Leznoff, C. Can. J. Chem. 1976, 54, 935-942.
(11) Farral, M. J.; Frechet, J. M. J. J. Org. Chem. 1976, 41, 3877-
3882.
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Org. Lett., Vol. 7, No. 5, 2005

BBN (Table 1). Reaction workup consisted simply of
concentrating the supernatant and passage through a short
silica plug (1:9 EtOAc/hexanes eluent). Solvent removal
provided the alcohol products in excellent purity, as deter-
mined by NMR comparison with authentic standards.
In the above hydroborations, PS-9-BBN was treated as
the limiting reagent and the alkene added in excess. For
applications with precious alkenes, higher conversions can
be achieved by using the resin in excess. Thus, when a 5-fold
excess of PS-9-BBN was used, the hydroboration/oxidation
of 1-octene and limonene proceeded in 86 and 89% yields,
respectively.
Scheme 3. Halogen Scavenging by PS-COD Resin
The precursor to PS-9-BBN, PS-COD (5), is an interesting
resin in its own right, as it is a high-loading resin with close
to 8 mmol/g of alkene functionality. Both bromine and iodine
add rapidly to PS-COD, and we have exploited this reactivity
by using PS-COD as a halogen-scavenging resin (Scheme
3). In the bromination of 1-octene and anthracence, excess
bromine was quenched after the reaction by the addition of
a 2-fold excess of PS-COD. The anthracene reaction involved
acetic acid as a solvent and quenching in this polar medium
by the polstyrene-based resin is sluggish. However, addition
of THF as a cosolvent resulted in fast scavenging. The other
example shown illustrates the removal of excess iodine from
an iodolactonization reaction.
Both resins feature high loadings (>3 mmol/g) and are
readily prepared in large scale by a simple and concise route
from inexpensive reagents.
Acknowledgment. The Combinatorial Centre of Excel-
lence was funded by an industrial consortium comprising
Amersham, AstraZeneca, GlaxoSmithKline, Lilly, Novabio-
chem, Organon, Pfizer, and Roche and government funding
through the JIF initiative.
In summary, we report the synthesis of two new polymer-
supported reagents containing novel functionality (1,5-diene
for PS-COD, dialkylborane for PS-9-BBN). We show that
PS-COD is useful as a halogen scavenger, and it is likely to
have additional applications as a diene ligand for organo-
metallic complexes. PS-9-BBN functions as a hydroborating
reagent in the same way as its solution-phase counterpart.
Supporting Information Available: Experimental pro-
cedures for the preparation of PS-COD and PS-9-BBN and
their use in halogen scavenging and hydroboration/oxidation,
respectively. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL047458G
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