(22 ЊC) over 2 h. The beads were then filtered and washed
with THF (3 × 5 min), CH2Cl2 : MeOH 1 : 1 (3 × 5 min), CH2Cl2
(5 × 5 min), and dried under reduced pressure to give free-
flowing, white beads. Larger beads (400–500 µm or 500–600 µm;
Stratospheres (from Polymer Laboratories Ltd; PL-PBS resin)
require 12 hours to metallate completely throughout the beads.
Acknowledgements
Financial support from BBSRC and GSK is acknowledged
gratefully.
Notes and references
1 S. L. Schreiber, Science, 2000, 287, 1964; D. R. Spring, Org. Biomol.
Chem., 2003, 1, 3867; M. D. Burke and S. L. Schreiber, Angew.
Chem., Int. Ed., 2004, 43, 46.
2 S. V. Ley, I. R. Baxendale, R. N. Bream, P. S. Jackson, A. G. Leach,
D. A. Longbottom, M. Nesi, J. S. Scott, R. I. Storer and S. J. Taylor,
J. Chem. Soc., Perkin Trans. 1, 2000, 3815.
3 Derivatized polystyrene can be synthesized either by copolymeriz-
ation (styrene, divinylbenzene & functionalized styrene) or, more
divergently, by functionalization of a polystyrene starting material.
4 Beads smaller than 75 µm have the advantage that chemical reaction
rates on polymer-supported substrates are faster relative to larger
beads; however, they have the major disadvantages that they are
more difficult to handle (filtration, flow characteristics, relative
avoidance of the effects of static, ease of compartmentalization into
porous capsules and cartridges) and have a much lower capacity of
functionality per bead.
5 G. Thomas and D. R. Spring, unpublished results. Bead sizes for
previous metallation procedures are given in refs. 6 and 7. Suzuki–
Miyaura cross-coupling is successful with large beads (see ref. 10).
6 T. M. Fyles and C. C. Leznoff, Can. J. Chem., 1976, 54, 935 (38–75
µm polystyrene).
7 Lithium–bromine exchange: M. J. Farrall and J. M. J. Fréchet,
J. Org. Chem., 1976, 41, 3877 (38–75 µm); G. D. Darling and J. M. J.
Fréchet, J. Org. Chem., 1986, 51, 2270 (38–75 µm); P. A. Tempest
and R. W. Armstrong, J. Am. Chem. Soc., 1997, 119, 7607 (38–75
µm); R. J. Kell, P. Hodge, M. Nisar and R. T. Williams, J. Chem.
Soc., Perkin Trans. 1, 2001, 3403; magnesium–bromine exchange:
S. Itsuno, G. D. Darling, H. D. H. Stöver and J. M. J. Fréchet, J. Org.
Chem., 1987, 52, 4645 (38–75 µm); M. Abarbri, J. Thibonnet,
L. Bérillon, F. Dehmel, M. Rottländer and P. Knochel, J. Org.
Chem., 2000, 65, 4618 (75–150 µm); calcium–bromine exchange:
R. A. O’Brien, T. Chen and R. D. Rieke, J. Org. Chem., 1992, 57,
2667 (38–75 µm); zinc–iodine exchange: Y. Kondo, T. Komine,
M. Fujinami, M. Uchiyama and T. Sakamoto, J. Comb. Chem.,
1999, 1, 123.
General procedure for alcohol attachment
Dry silane polystyrene 3 (1.6 mequiv gϪ1) was added to a dry,
fritted polypropylene column (Bruker) fitted with a Teflon
stopcock and capped with a suba seal. The vessel was evacuated
and purged with Ar. The beads were swollen with CH2Cl2
(10 ml per gram of beads) and TMSCl (6 equiv.) and occasion-
ally agitated over 30 min, at room temperature, under Ar. The
solution was then drained under positive Ar pressure, and
washed/drained three times with anhydrous CH2Cl2. The beads
were then suspended in a CH2Cl2 solution of 1,3-dichloro-5,5-
dimethylhydantoin (3 equiv.) and agitated occasionally over 2 h,
at room temperature, under Ar. The solution was then drained
under positive Ar pressure, and washed/drained two times with
anhydrous CH2Cl2 to give 4. The silyl chloride beads were
suspended in a CH2Cl2 solution of 2,6-lutidine (4 equiv.),
DMAP (0.1 equiv.) and anhydrous alcohol (3 equiv.; 1.5 equiv.
can be used if the alcohol is valuable), the mixture was agitated
then left to stand overnight, at room temperature, under Ar.
The solution was then drained under positive Ar pressure
(excess alcohol can be recovered), and washed/drained as in
ref. 10. The beads were air-dried under suction for 2 h with
occasional agitation, and then placed under high vacuum.
General procedure for alcohol cleavage
The beads (100 mg) were swollen in THF (0.5 ml) and HFؒPyr
(50 µl, 1.77 mmol) was added. The vials were sealed and
agitated for 2.5 h, then quenched using trimethylethoxysilane.
The vials were agitated for a further 30 min to ensure complete
quenching. Then the solvent was filtered through a plug of
silica gel and the resin washed with CH2Cl2. The solvent
was removed in vacuo and the product purified by column
chromatography.
8 The use of copolymerized bromopolystyrene (styrene, divinyl-
benzene & 4-bromostyrene) ensures that the bromine functionalis-
ation occurs uniformly throughout the polymer bead. Commercially
available polymers are available in a range of bead sizes, from 38–75
µm (400–200 mesh) to 500–600 µm (35–30 mesh).
9 K. Kitagawa, A. Inoue, H. Shinokubo and K. Oshima, Angew.
Chem., Int. Ed., 2000, 39, 2481.
10 The metallated polymer could be transmetallated also, e.g. with
copper (CuCNؒ2LiBr) or zinc (ZnCl2), before addition of the elec-
trophile. In Scheme 2 the cuprate was made before addition of allyl
bromide.
11 F. X. Woolard, J. Paetsch and J. A. Ellman, J. Org. Chem., 1997, 62,
6102; J. A. Tallarico, K. M. Depew, H. E. Pelish, N. J. Westwood,
C. W. Lindsley, M. D. Shair, S. L. Schreiber and M. A. Foley,
J. Comb. Chem., 2001, 3, 312; P. A. Clemons, A. N. Koehler,
B. K. Wagner, T. G. Sprigings, D. R. Spring, R. W. King,
S. L. Schreiber and M. A. Foley, Chem. Biol., 2001, 8, 1183.
12 The theoretical maximum silicon content in product polymer =
5.2%.
General Mitsunobu reaction procedure
To a mixture of carboxylic acid (1 equiv.), alcohol (1.5 equiv.)
and polymer bound triphenylphosphine (0.9 mequiv gϪ1, 1.5
equiv.) in THF (ca. 0.1 M) under nitrogen at 0 ЊC was added
di-tert-butyl azodicarboxylate (1.5 equiv.) in THF (1 ml). The
reaction was warmed to room temperature and stirred over-
night. Extra polymer bound triphenylphosphine (0.5 equiv.)
was added to scavenge remaining tert-butyl azodicarboxylate
and the mixture stirred for a further 30 min. The reaction was
filtered and the resins washed with CH2Cl2. The organic filtrate
was washed with 3 M HCl (× 2), brine (× 2) dried (MgSO4),
filtered and concentrated in vacuo. The crude product was
purified by column chromatography using CH2Cl2 as the eluent
to yield a colourless oil.
13 Ethoxytrimethylsilane (bp = 75 ЊC), ethanol (bp = 79 ЊC), pyridine
(bp = 115 ЊC) and trimethylsilyl fluoride (bp = 16 ЊC) can all be
removed under reduced pressure.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 7 9 – 1 6 8 1
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