Reusable resin plug-bound palladium catalysts for organic synthesis

Article abstract of DOI:10.1016/S0040-4039(03)00977-8

Resin plugs, a unique and conveniently handled form of resin, prepared by sintering high-density polyethylene (HDPE) with pre-functionalised resins, were derivatised and loaded with palladium(0). These 'plugs' were used in the preparation of a Suzuki reaction based library and the removal of allyl ester protecting groups. The 'plugs of catalyst' were easily separated from the reaction mixture and were re-used multiple times with minimal loss of activity.

Full text of DOI:10.1016/S0040-4039(03)00977-8

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TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4779–4782
Reusable resin plug-bound palladium catalysts for organic
synthesis
Butrus Atrash,a John Readerb and Mark Bradleya,*
aCombinatorial Centre of Excellence, Department of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
bMillennium Pharmaceuticals, Granta Park, Great Abington, Cambridge CB1 6ET, UK
Received 11 February 2003; revised 7 April 2003; accepted 16 April 2003
Abstract—Resin plugs, a unique and conveniently handled form of resin, prepared by sintering high-density polyethylene (HDPE)
with pre-functionalised resins, were derivatised and loaded with palladium(0). These ‘plugs’ were used in the preparation of a
Suzuki reaction based library and the removal of allyl ester protecting groups. The ‘plugs of catalyst’ were easily separated from
the reaction mixture and were re-used multiple times with minimal loss of activity. © 2003 Elsevier Science Ltd. All rights
reserved.
Over the past decade, small molecule solid-phase syn-
thesis has become an important part of the drug discov-
ery process.1 One reaction that has been highly
favoured in solid-phase applications is the formation of
biaryls via the palladium-catalysed Suzuki cross-cou-
pling reactions of aryl halides or aryl triflates with
arylboronic acids.2 This is due, in part, to the observa-
tion that compounds containing the biaryl group have
shown diverse spectra of biological activities. Thus
compounds incorporating this structural motif3 have
been shown to possess angiotensin II antagonism, tubu-
lin binding properties and estrogenic activity as well as
being found in natural products with antitumour and
antiviral activities.
Usually, a soluble palladium catalyst is used in the
Suzuki reaction such as Pd(PPh3)4. However, recovery
of the palladium catalyst is often a costly and inconve-
nient process. Industrially, palladium catalysts are
recovered by precipitation or by the use of water-solu-
ble phosphine ligands or at least the metal itself can be
recovered by the formation of insoluble complexes,4
hence the desirability of heterogeneous catalysts is obvi-
ous. Polystyrene (crosslinked with divinylbenzene) sup-
ported palladium catalysts have in the past been
successfully used for a variety of organic reactions such
as hydrogenations,5 allylic substitutions,6 isomerisa-
tion,7 decarboxylations8 and for the Heck reaction.9
Hallberg and co-workers for example investigated vari-
ous carbonꢀcarbon bond forming reactions such as the
Heck arylation,10 using such supported catalysts. More
recently, there have been reports on the preparation
and utilisation of a number of highly effective polymer-
supported palladium catalysts, which are easily recover-
able and re-usable, the most striking of these methods
being
the
‘micro-encapsulation’
methods
of
Kobayashi.11 Soluble palladium complexes are nor-
mally used to introduce the Pd metal by exchange
reactions with appropriate functionality on the
polystyrene backbone. Anderson,12 for example, pre-
pared a heterogeneous catalyst for the Heck reaction in
two steps by first substituting Merrifield resin with
Figure 1. A palladium-loaded ‘plug’.
Keywords: resin plugs; catalysis; solid-phase synthesis; Suzuki cou-
pling.
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00977-8

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B. Atrash et al. / Tetrahedron Letters 44 (2003) 4779–4782
Scheme 1. Synthesis of catalyst ‘plugs’.
2. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; (b)
Suzuki, A. J. Organomet. Chem. 1999, 576, 147; (c)
Advances in Metal-Organic Chemistry; Miyaura, N., Ed.;
JAI: London, 1998; Vol. 6, p. 187; (d) Stanforth, S. P.
Tetrahedron 1998, 54, 263; (e) Metal Catalyzed Cross
Coupling Reactions; Suzuki, A., Ed.; Wiley-VCH: New
York, 1998; Chapter 2.
Ph2PLi followed by an exchange reaction with
PdCl2(PhCN)2.
We have recently published13 details of a new solid
support (resin plugs) for solid-phase synthesis (see Fig.
1). Here the results on the use of this support for
palladium catalysed reactions are reported. The resin
‘plugs’ (high-density polyethylene (HDPE) co-sintered
with Merrifield resin, cross-linked with 2% divinylben-
zene) were first substituted with Ph2PLi, followed by an
exchange reaction with Pd(PPh3)4 to provide the palla-
dium supported resin plugs which were black in colour
(Scheme 1).14
3. (a) Sato, T. Bull. Chem. Soc. Jpn. 1959, 32, 1130; (b) Sato,
T.; Oki, M. Bull. Chem. Soc. Jpn. 1959, 32, 1289; (c) Sato,
T.; Oki, M. Bull. Chem. Soc. Jpn. 1959, 32, 1292; (d) Bovy,
P. R.; Collins, J. T.; Olins, G. M.; McMahon, E. G.;
Hutton, W. C. J. Med. Chem. 1991, 34, 2410; (e) Mantlo,
N. B.; Chakravarty, P. K.; Ondeyka, D. L.; Siegl, P. K.
S.; Chang, R. S.; Lotti, V. J.; Faust, K. A.; Chen, T.-B.;
Schorn, T. W.; Sweet, C. S.; Emmert, S. E.; Patchett, A.
A.; Greenlee, W. J. J. Med. Chem. 1991, 34, 2919; (f)
Blankey, C. J.; Hodges, J. C.; Klutchko, S. R.; Himmels-
bach, R. J.; Chucholowski, A.; Connolly, C. J.; Neergaard,
S. J.; Van Nieuwenhze, M. S.; Sebastian, A.; Quin, J., II;
Essenburg, A. D.; Cohen, D. M. J. Med. Chem. 1991, 34,
3248; (g) Okuda, T.; Yoshida, T.; Hatano, T. In Phenolic
Compounds in Food and their Effects on Health II; Huang,
M.; Ho, C.; Lee, C., Eds.; ACS Symposium Series 507;
American Chemical Society: Washington, DC, 1992;
Chapter 13, p. 160; (h) Thomas, A. P.; Allott, C. P.;
Gibson, K. H.; Major, J. S.; Masek, B. B.; Oldham, A. A.;
Ratcliffe, A. H.; Roberts, D. A.; Russell, N. T.; Thomason,
D. A. J. Med. Chem. 1992, 35, 877; (i) Banwell, M. G.;
Cameron, J. M.; Corbett, M.; Dupuche, J. R.; Hamel, E.;
Lambert, J. N.; Lin, C. M.; Mackay, M. F. Aust. J. Chem.
1992, 45, 1967; (j) Chang, L. L.; Ashton, W. T.; Flanagan,
K. L.; Strelitz, R. A.; MacCoss, M.; Greenlee, W. J.;
Chang, R. S. L.; Lotti, V. J.; Faust, K. A.; Chen, T.-B.;
Bunting, P.; Zingaro, G. J.; Kivlighn, S. D.; Siegl, P. K.
S. J. Med. Chem. 1993, 36, 2558.
The activity of the resin plug catalysts for Suzuki
reactions was first measured on a standard reaction: the
coupling of phenylboronic acid with 4-bromopyridine
(Scheme 2). The plug (0.05 equiv. of catalyst) was
placed into the reaction vessel, which was shaken or
stirred for 24 hours. The ‘plug’ was removed with
tweezers and washed with solvent. The same resin
‘plug’ was recycled, carrying out the identical reaction
four times. The isolated yields of purified product were:
92, 90, 86 and 85%, respectively.
The plugs were used in the synthesis of a small library
of biaryl compounds, while at the same time preparing
an identical series of compounds using soluble
Pd(PPh3)4 as the catalyst to compare yields. The results,
as summarized in Table 1, show that the yields were
almost identical.
In a further application of the ‘plug’ supported palla-
dium catalysts, Boc-Phe-OAllyl was synthesized and the
allyl ester was removed quantitatively by refluxing in
THF for 24 h using 0.05 equiv. of catalyst and 1 equiv.
of pyrrolidine.
4. Tsuji, J. Palladium Reagents and Catalysts; Wiley:
Chichester, 1995.
5. (a) Terasawa, M.; Kaneda, K.; Imanaka, T.; Teranishi, S.
J. Catal. 1978, 51, 406; (b) Bar-Sela, G.; Warshawsky, A.
J. Poly. Sci., Part A: Poly. Chem. 1990, 28, 1303; (c) Zhang,
Y.; Liao, S.; Xu, Y. Tetrahedron Lett. 1994, 35, 4599; (d)
Selvaraj, P. C.; Mahadevan, V. J. Poly. Sci., Part A: Poly.
Chem. 1997, 35, 105.
6. (a) Trost, B. M.; Warner, R. W. J. Am. Chem. Soc. 1982,
104, 6112; (b) Bergbreiter, D. E.; Lynch, T. J. J. Org. Chem.
1983, 48, 4179; (c) Bergbreiter, D. E.; Weatherford, D. A.
J. Org. Chem. 1989, 54, 2726.
In summary, the ‘plug’-bound palladium catalysts
provide a reusable and much easier to handle alterna-
tive to the homogenous analogue Pd(PPh3)4 while
maintaining comparable catalytic activity. The catalyst
‘plug’ could also be utilized for the clean removal of the
allyl ester and allyloxycarbonyl protecting groups.
Importantly the ‘plugs’ remove the need for any purifi-
cation following their use.
7. (a) King, R. B.; Hanes, R. M. J. Org. Chem. 1979, 44, 1092;
(b) Card, R. J.; Neckers, D. C. J. Org. Chem. 1978, 43,
2958.
References
8. Bergbreiter, D. E.; Chen, B.; Weatherford, D. J. Mol.
Catal. 1992, 74, 409.
1. (a) Gordon, E. M.; Barrett, W. J.; Fodor, S. P. A.; Gallop,
M. A. J. Med. Chem. 1994, 37, 1233; (b) Dolle, R. E. J.
Comb. Chem. 2001, 3, 477.
9. (a) Kaneda, K.; Terasawa, M.; Imanaka, T.; Teranishi, S.
Fundam. Res. Homogeneous Catal. 1979, 3, 671; (b)
Kaneda, K.; Terasawa, M.; Imanaka, T.; Teranishi, S. J.

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B. Atrash et al. / Tetrahedron Letters 44 (2003) 4779–4782
4781
Scheme 2. Standard Suzuki coupling reaction.
Table 1. Comparison of yields for the formation of the biaryl compounds with the ‘plug’ based and soluble Pd(PPh3)4
catalysts
aThe figures in brackets are the yields obtained with Pd(PPh3)4. All based on 0.05 equiv. of catalyst. All compounds gave satisfactory analytical
data.15

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4782 B. Atrash et al. / Tetrahedron Letters 44 (2003) 4779–4782
Organomet. Chem. 1978, 162, 403; (c) Anderson, C. M.;
Karabelas, K.; Zhang, Z. Y.; Hu, H. W.; Kao, T. Y.
Synth. Commun. 1990, 20, 3563; (d) Liao, Y.; Zhang, Z.
Y.; Hu, H. W. Synth. Commun. 1995, 25, 595.
(2×), CHCl3 (2×), benzene (2×) and ether (2×). The plugs
were then suspended in benzene (50 ml) and Pd(PPh3)4
(2.8 g, 2.4 mmol) was added. The mixture was heated at
reflux under N2 for 24 h. After filtration, the plugs were
washed successively with ethanol (3×), ether (3×) and
dried.
10. Hallberg, A.; Anderson, C. J. Org. Chem. 1985, 50, 3891.
11. (a) Jang, S. B. Tetrahedron Lett. 1997, 38, 1793; (b) Le
Drian, C.; Fenger, I. Tetrahedron Lett. 1998, 39, 4287.
12. Anderson, C.; Larsson, R. J. Catal. 1983, 81, 179 and
194.
13. Atrash, B.; Bradley, M.; Kobylecki, R.; Cowell, D.;
Reader, J. Angew. Chem., Int. Ed. 2001, 40, 938.
14. In a typical procedure, 30 resin plugs (HDPE, co-sintered
with Merrifield resin (crosslinked with 2% DVB, 2.4
mmol) were suspended in dry THF (60 ml). To this
suspension was then added a solution of LiPPh2 (12
mmol) in dry THF (10 ml). The suspension was gently
stirred at 25°C under N2 for 24 h. Acetone/H2O (3:1, 100
ml) was added and the plugs filtered. These were then
successively washed with water/acetone (2×), acetone
15. Selected data: 11 lH (300 MHz, DMSO-d6) 7.00 (2H, d,
J 8, Ar), 7.27 (1H, t, J 7, Ar), 7.40 (2H, t, J 7, Ar), 7.49
(2H, d, J 7, Ar), 7.57 (2H, d, J 8, Ar), 9.70 (1H, s, OH);
lC (75 MHz, DMSO-d6) 157.60, 140.70, 131.41, 128.96,
128.18, 126.41, 116.20, 115.85; TLC Rf 0.5 (9:1 hex-
ane:EtOAc); ES-MS (-ve): m/z 169 (M−H); 14 lH (300
MHz, DMSO-d6) 2.02 (3H, s, CH3CO), 3.73 (3H, s,
CH3O), 6.90 (2H, d, J 8, Ar), 7.45 (2H, d, J 8.5), 7.55
(2H, d, J 5.5, Ar), 7.63 (2H, d, J 5, Ar), 9.90 (1H, s, NH);
lC (75 MHz, DMSO-d6) 168.67, 159.01, 138.62, 134.89,
132.67, 127.73, 126.75, 119.80, 114.76, 55.56, 24.46; TLC
Rf 0.4 (9:1 hexane:EtOAc); ES-MS (+ve): m/z 242 (M+
H)+, 264 (M+Na)+.