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48. Linkletter, B. A.; Bruice, Ò. C. Solid-Phase Synthesis of Oligomeric De-oxynucleic Guanidine (DNG): A Polycationic Analogue of DNA, Bioorg. Med Chem. Lett. 1998, 8, 1285-1290.
49. Zhong, H. Ì.; Greco, M. N.; Maryanoff, Â. E. Solid-Phase Synthesis of Arginine-Containing Peptides by Guanidine Attachment to a Sulfony Linker, J. Org. Chem. 1997, 62, 9326-9330.
50. Bonnat, Ì.; Bradley, Ì.; Kilburn, J. D. The Solid Phase Synthesis of a Guanidinium Based “Tweezer” Receptor, Tetrahedron Lett. 1996,37,54095412.
51. Schneider, S. E.; Bishop, P. A.; Salazar, M. A.; Bishop, O. A.; Anslyn, E. V. Solid Phase Synthesis of Oligomeric Guanidiniums, Tetrahedron 1998, 54, 15063.
Solid-Phase Organic Synthesis. Edited by Kevin Burgess Copyright © 2000 John Wiley & Sons, Inc. ISBNs: 0-471-31825-6 (Hardback); 0-471-22824-9 (Electronic)
PALLADIUM-CATALYZED CARBON-CARBON BOND FORMATION ON SOLID SUPPORT
MATTHEW H. TODD and CHRIS ABELL University Chemical Laboratory
Palladium-catalyzed carbon-carbon bond formation has emerged as one of the most powerful methods in organic synthesis. Consequently, it is unsurprising that adaptation of such methods to the solid phase is an important initiative. Many pharmacophores and scaffolds are directly accessible with simple palladium-catalyzed chemistry, for example, the biaryl subunit,1 which has also been used as the template for a “universal library.”2
26 PALLADIUM-CATALYZED CARBON-CARBON BOND FORMATION ON SOLID SUPPORT
Several features of palladium-catalyzed carbon-carbon bond formation reactions are attractive in high-throughput chemistry. These reactions tend to be
• possible at ambient temperature and pressure, under nonanhydrous conditions, and with exposure to the atmosphere, hence amenable to automation;
• high yielding for a range of substrate types;
• tolerant of a range of solvents. Solvent is a major consideration for any solid-phase reaction as the choice can be compromised by the solid phase. Usually the solvent of choice is one which swells the support well, allowing access to internal sites. It is interesting to note that since much solid-phase chemistry is conducted on hydrophobic polystyrene-type supports, there are few examples to date of purely aqueous solid-phase palladium-catalyzed reactions. These have been shown to proceed extremely well in solution, often with accelerated rates and lower catalyst levels than the related reactions in organic solvents;3
• flexible with respect to which component is used in solution and which is anchored to the solid phase.
This review is divided into four main sections, covering the Heck, Stille, and Suzuki reactions, with miscellaneous reactions being included at the end. Processes featuring alkynes in copper co-catalyzed Sonogashira-type couplings have been included in the section on Heck reactions.4 This review does not cover carbon-carbon bond formation processes using immobilized catalysts.5-7 Similarly, fluorous-phase syntheses8-11 and those on polyethylene glycol12-14 are excluded.
2.1.1. Practical Considerations
Some special considerations apply when palladium complexes are to be used in solid-phase chemistry. Two obvious concerns are penetration of relatively large palladium complexes into resins and the effects of the resin microenvironment on dissociation of ligands from fully coordinated palladium complexes to give active species. The success of the chemistry reported to date has been an empirical test of these questions, but such factors may explain instances in which, for example, the ligandless
2.2. HECK REACTION 27
Pd2(dba)3 catalyst is preferred over the more congested Pd(PPh3)4. Moreover, some reaction protocols allow for diffusion of the palladium catalyst into the resin prior to addition of other reagents.
Removal of palladium at the end of solid-phase reactions has been achieved in different ways. Palladium can be washed away from the support with the other excess reagents and by-products, but complications can arise as a result of palladium appearing in cleaved products even after washing (which has necessitated brief chromatography for purification), or palladium black deposition during the course of the chemistry. For example, we have observed that palladium-catalyzed processes on chloromethyl resin that still contains unsubstituted sites leads to palladium black deposition [possibly due to insertion of palladium (0) into the CH2C1 bond], whereas the same resin lacking redundant chloromethyl sites presented no such difficulties.15 Ellman introduced a KCN/DMSO wash to remove deposited palladium, a strategy that has been adopted by others (see below). In general, while inexpensive reagents may be used in excess for solid-phase reactions to drive them to completion, the levels of palladium catalyst need not be increased proportionally. Often the level of catalyst may be slightly increased from, say, 5 to 20 mol %, but the palladium is always still sub-stoichiometric. This reduces the expense and problems of disposal.