Soluble polymer-supported

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. 

In 2004, Weberskirch and co-workers tried a new approach by synthesising [RhBr(COD)(NHC)] 23 (NHC = l-(2 -hydroxyethyl)-3-methylimidazolidine-2-ylidene) [28]. Subsequently, attaching the unsymmetrical, monohydroxy-functionalised NHC by ester groups to an amphiphilic, water-soluble polymer support (ps)... 

Geckeler, K, E, Soluble Polymer Supports for Liquid-Phase Synthesis. VoL 121, pp. 31-80. Gehrke, S, H. Synthesis, Equilibrium Swelling, Kinetics Permeability and Applications of Environmentally Responsive Gels. Vol. 110, pp. 81 -144. de GenneSy P.-G> Flexible Polymers in Nanopores. VoL 138, pp. 91-106. 

Fig. 2. Lysine-based dendron 1 of 2nd generation and a similar dendron 2 of 4th generation with PEG as soluble polymer support [8,9]...

Scheme 7.61 Principles of syntheses on soluble polymer supports.

Several microwave-assisted protocols for soluble polymer-supported syntheses have been described. Among the first examples of so-called liquid-phase synthesis were aqueous Suzuki couplings. Schotten and coworkers presented the use of polyethylene glycol (PEG)-bound aryl halides and sulfonates in these palladium-catalyzed cross-couplings [70]. The authors demonstrated that no additional phase-transfer catalyst (PTC) is needed when the PEG-bound electrophiles are coupled with appropriate aryl boronic acids. The polymer-bound substrates were coupled with 1.2 equivalents of the boronic acids in water under short-term microwave irradiation in sealed vessels in a domestic microwave oven (Scheme 7.62). Work-up involved precipitation of the polymer-bound biaryl from a suitable organic solvent with diethyl ether. Water and insoluble impurities need to be removed prior to precipitation in order to achieve high recoveries of the products. 

The soluble polymer support was dissolved in dichloromethane and treated with 3 equivalents of chloroacetyl chloride for 10 min under microwave irradiation. The subsequent nucleophilic substitution utilizing 4 equivalents of various primary amines was carried out in N,N-dimethylformamide as solvent. The resulting PEG-bound amines were reacted with 3 equivalents of aryl or alkyl isothiocyanates in dichloromethane to furnish the polymer-bound urea derivatives after 5 min of micro-wave irradiation (Scheme 7.75). After each step, the intermediates were purified by simple precipitation with diethyl ether and filtration, so as to remove by-products and unreacted substrates. Finally, traceless release of the desired compounds by cyclative cleavage was achieved under mild basic conditions within 5 min of micro-wave irradiation. The 1,3-disubstituted hydantoins were obtained in varying yields but high purity. 

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... 

Geckeler, K. E. Soluble Polymer Supports for Li quid-Phase Synthesis. Vol. 121, pp. 31-80. 

Highly functionalized tetraaryl-4,5-dihydro-l,2,4-triazoles 118a-y have been prepared on a soluble polymer support (PEG4000) from the cycloaddition of diarylimines with a nitrile imine, prepared in situ from the arylhydra-zone 119. The triazole products are highly fluorescent and several have reasonable fluorescence quantum yields (Scheme 8 and Table 19) <2005S3535>. 

Lithium ester enolate addition to imines has been used for the construction of optically active p-lactams, e.g. 64 and the lithium enolates have been found to be superior to other metal derivatives for both yields and diastereoselectivity in some cases <00H(53)1479>. Immobilized lithium ester enolates have been utilized for the first time <00OL907> and soluble polymer supported imines were used to obtain N-unsubstituted azetidin-2-ones under mild conditions <00CEJ193>. Both lithium and titanium enolates have been employed to obtain cholesterol absorption inhibitors <99TA4841>. Lithium ynolates 65 add to imines to provide P-lactams in good to excellent yield <00TL5943>. 

The multipolymer enzymatic resolution of soluble polymer-supported alcohols 42 and 43 was achieved using an immobilised lipase from Candida Antarctica (Novozym 435). The R-alcohol was obtained in enantiomerically pure form (>99% ee) after its cleavage from the poly(ethylene) glycol (PEG) scaffold . The achiral hydantoin- and isoxazoline-substituted dispirocyclobutanoids 47 were produced using both solution and solid-phase synthesis <00JOC3520, OOCC1835>. 

An efficient one-pot synthesis of isoxazolines, using soluble polymer-supported acrylate has been described (174). Thus, the addition of 1,4-benzenedicarbonitrile N,N -dioxide (generated from N, N -dihydroxy-1,4-benzenedicarboximidoy 1 dichloride) to polyethylene glycol-supported 2-propenoic acid 2-hydroxyethyl ester 32 (P = polyethylene glycol support) followed by cleavage of the bond with the support gave 3,3/-(l,4-phenylene)bis[4,5-dihydro-5-isoxazolecarboxylic acid] di-Me ester (33) in 97% yield. 

Scheme 1.6 The first approaches to oligosaccharide synthesis employing soluble polymer supports.

Soluble polymer-supported (i )-BINAP ligands were employed for the preparation of the Ru -bearing catalysts (54) and (55) which are shown in Scheme 4.33 [126]. Both these catalysts exhibited high activity and enantioselectivity in the asymmetric hydrogenation of 2-(6 -methoxy-2 -naphthyl)propenoic add. 

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