Soluble Polymer-Supported Reactions

Soluble polymers, such as polyethylene glycol (PEG), can be used in similar ways to the insoluble supports, but they generally require a more elaborate work-up, often involving precipitation of the polymeric 

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Abstract Current microwave-assisted protocols for reaction on solid-phase and soluble supports are critically reviewed. The compatibility of commercially available polymer supports with the relatively harsh conditions of microwave heating and the possibilities for reaction monitoring are discussed. Instrmnentation available for microwave-assisted solid-phase chemistry is presented. This review also summarizes the recent applications of controlled microwave heating to sohd-phase and SPOT-chemistry, as well as to synthesis on soluble polymers, fluorous phases and functional ionic liquid supports. The presented examples indicate that the combination of microwave dielectric heating with solid- or soluble-polymer supported chemistry techniques provides significant enhancements both at the level of reaction rate and ease of purification compared to conventional procedures. 

By replacing insoluble cross-linked resins with soluble polymer supports, the well-estabhshed reaction conditions of classical organic chemistry can be more readily apphed, while still fadhtating product purification. However, soluble supports suffer from the hmitation of low loading capacity. The recently introduced fluorous synthesis methodology overcomes many of the drawbacks of both the insoluble beads and the soluble polymers, but the high cost of perfluoroalkane solvents, hmitation in solvent selection, and the need for specialized reagents may hmit its apphcations. 

Several microwave-assisted procedures have been described for soluble polymer-supported syntheses. Polyethylene glycol) (PEG)-supported aryl bromides have been shown to undergo rapid palladium(0)-catalyzed Suzuki couplings with aryl boronic acids in water (Scheme 12.16) [63], The reaction proceeded without organic cosolvent... 

Initially, the term Hquid-phase synthesis was used to contrast the differences between soHd-phase peptide synthesis and a method of synthesis on soluble polyethylene glycol (PEG) [5, 6]. Although soluble polymer-supported synthesis is less ambiguous than Hquid-phase synthesis, the latter term is more prevalent in the Hterature. In-keeping with previous reviews [7-12], the phrases classical or solution synthesis will be used to describe homogeneous reaction schemes that do not employ polymer supports while liquid-phase synthesis will be reserved... 

A frequent complication in the use of an insoluble polymeric support lies in the on-bead characterization of intermediates. Although techniques such as MAS NMR, gel-phase NMR, and single bead IR have had a tremendous effect on the rapid characterization of solid-phase intermediates [27-30], the inherent heterogeneity of solid-phase systems precludes the use of many traditional analytical methods. Liquid-phase synthesis does not suffer from this drawback and permits product characterization on soluble polymer supports by routine analytical methods including UV/visible, IR, and NMR spectroscopies as well as high resolution mass spectrometry. Even traditional synthetic methods such as TLC may be used to monitor reactions without requiring preliminary cleavage from the polymer support [10, 18, 19]. Moreover, aliquots taken for characterization may be returned to the reaction flask upon recovery from these nondestructive... 

Soluble polymer-bound catalysts for epoxidation reactions have also been explored, with a complete study into the nature of the polymeric backbone performed by Janda [70]. Chiral (salen)-Mn complexes were appended to MeO-PEG, NCPS, Jan-daJeF and Merrifield resin via a glutarate spacer. It was found that for the Jacobsen epoxidation of ds-/ -mefhylstyrene, the enantioselectivities for each polymer-supported catalyst were comparable (86-90%) to commercially available Jacobsen catalyst (88%). Both soluble polymer-supported catalysts could be used twice before a decline in yield and enantioselectivity was observed. However, neither soluble polymer support proved as suitable as the insoluble JandaJel-supported (salen)-Mn complex for the epoxidation because residual impurities during precipitation and leaching of Mn from the complex, resulted in lowered yields. 

Oikawa M, Ikoma M, Sasaki M (2005) Parallel synthesis of tandem Ugi/Diels-Alder reaction products on a soluble polymer support directed toward split-pool realization of a small molecule library. Tetrahedron Lett 46 415-418... 

Zinc chloride-doped natural phosphate was shown to have catalytic behavior in the 1,3-dipolar cycloadditions of nucleoside acetylenes with azides to form triazolonucleosides <99SC1057>. A soluble polymer-supported 1,3-dipolar cycloaddition of carbohydrate-derived 1,2,3-triazoles has been reported <99H(51)1807>. 2-Styrylchromones and sodium azide were employed in the synthesis of 4(5)-aryl-5(4)-(2-chromonyl)-1,2,3-triazoles <99H(51)481>. Lead(IV) acetate oxidation of mixed bis-aroyl hydrazones of biacetyl led to l-(a-aroyloxyarylideneamino)-3,5-dimethyl-l,2,3-triazoles <99H(51)599>. Reaction of 1-amino-3-methylbenzimidazolium chloride with lead(fV) acetate afforded l-methyl-l/f-benzotriazole <99BML961>. Hydrogenation reactions of some [l,2,3]triazolo[l,5-a]pyridines, [l,2,3]triazolo[l,5-a]quinolines, and [l,2,3]triazolo[l,5-a]isoquinolines were studied <99T12881>. 

Diels-Alder reactions mediated by FeCh-Nal <2004TL3507> or sulfamic acid <2004S69, 2004S949> yield tetrahydroquinolines while the use of polyethylene glycol 4000 (PEG 4000) as a soluble polymer support in a three-step one-pot aza-Diels-Alder reaction also gives tetrahydroisoquinolines <2004SL1175>. 

The catalytic performance of the fluoropolymer ligands 1 and 2 was first tested in the fluorous biphase hydroformylation of 1-alkenes, styrene and n-butyl acrylate. The reaction was conducted in a batch reactor in a 40/20/40 vol% hexane/toluene/perfluoromethylcyclohexane solvent mixture (10 mL). The catalyst was formed in situ by adding [Rh(CO)2(acac)] (5 rmol, P/Rh = 6) to the polymer-containing solvent mixture followed by introduction of syngas (30 bar, CO/H2 = 1/1). Table 2 summarises the results obtained. The salient features of the results are Firstly, the activity of the fluorous soluble polymer catalysts are significantly higher than that reported for solid polymer- and aqueous soluble polymer-supported rhodium catalysts.18-22 For example, the average turnover frequency (TOF) for the fluorous biphase hydroformylation of 1-decene is 136 mole aldehyde h-1 per mol of rhodium catalyst with an aldehyde selectivity of 99%. In comparison, a rhodium catalyst supported on the... 

Enholm [12] has also prepared an enantiomerically pure soluble polymer support 82 by couphng xylose-derived chiral auxiliary 81 with 77 (Scheme 18). The chiral support was then treated with bromopropionic acid 83 to give substrate 84. Eree radical allyl transfer from allyltributyltin imder thermal conditions provided 85 in 93% yield, and basic cleavage from the resin gave (R)-(-)-2-methylpent-4-enoic acid 86 in 80% yield and 97% ee, with a 92% yield of recovered 82. Previous studies of the same process in solution had found the addition of Lewis acids to be crucial for high selectivities to be obtained. Interestingly, the addition of Lewis acids to the reaction on polymer support led to cleavage of the carbohydrate from the polymer backbone. En-... 

Enholm [26] has reported the first examples of asymmetric radical cy-clizations on soluble polymer supports. The stereocontrol element employed consists of a (+)-isosorbide group attached by a 4-carbon chain to each subunit of a soluble succinimide-derived ROMP backbone. Treatment of the radical cychzation substrate 162 with tributyltin hydride in the presence of zinc chloride followed by hydrolysis of the resulting polymer-supported ester 163 gave the desired product 164 in 80% yield and > 90% ee (Scheme 38). The use of alternative Lewis acids, such as magnesium bromide etherate and ytterbiiun (III) triflate, resulted in lower enantioselectivities, 84% and 72% respectively. No such decrease in selectivity was observed in analogous reactions carried out off-support [27], suggesting that the polymer backbone is somehow responsible for this phenomenon. 

The soluble polymer-supported catalysts have also been used for asymmetrically catalyzed reactions Following a procedure for the preparation of insoluble polymeric chiral catalysts a soluble linear polystyrene-supported chiral rhodium catalyst has been prepared. This catalyst displays high enantiomeric selectivity compared to the low molecular weight catalyst. Thus, hydroformylation of styrene using this catalyst produces aldehydes in high yields. The branched chiral hy drotropaldehy de is formed in 95% selectivity. 

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