Support soluble

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. 

Keywords Microwave Heterocyclic Solid-phase Solid-support Soluble-support... 

In addition to the insoluble polymers described above, soluble polymers, such as non-cross-linked PS and PEG have proven useful for synthetic applications. However, since synthesis on soluble supports is more difficult to automate, these polymers are not used as extensively as insoluble beads. Soluble polymers offer most of the advantages of both homogeneous-phase chemistry (lack of diffusion phenomena and easy monitoring) and solid-phase techniques (use of excess reagents and ease of isolation and purification of products). Separation of the functionalized matrix is achieved by either precipitation (solvent or heat), membrane filtration, or size-exclusion chromatography [98,99]. 

PEG polymers are widely used as water soluble supports [99]. Although these polymers suffer from easy loss of PEG oligomers, they are frequently used for the preparation of small organic molecules [100-105] and biopolymers [106,107]. The main benefit of PEG supports is their solubility in water as well as most organic solvents. Also, as opposed to most solid-phase techniques, PEG polymers allow for easy on-bead NMR monitoring. Soluble PEG supports have been used frequently in synthetic microwave chemistry protocols [108-122]. 

In addition to the examples described above, functionalized ionic liquids have been recently introduced as microwave-compatible soluble supports [137,138]. 

Soluble support-based synthetic approaches offer the advantages of both homogeneous solution-phase chemistry (high reactivity, ease of analysis) and solid-phase synthesis (large excess of reagents, simple product isolation and purification) [98,99]. As a representative example, PEG, one of the most widely used soluble polymers, has good solubility in most organic solvents (i.e., dichloromethane, acetonitrile, dimethylformamide, and toluene), but it... 

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. 

Further examples of the creation of heterocycUc rings using microwave technology in combination with soUd or soluble supports are found in references [108-115,117,119,121,123,135,185]. 

The first example of microwave-promoted solid-phase methodology in heterocyclic chemistry was the arylation of thiophene and indole via Suzuki couplings on TentaGel S RAM resin, as demonstrated by Hallberg and coworkers in 1996, before temperature- and pressure-controlled microwave instruments were even available [189]. Three years later Schotten and coworkers presented analogous but aqueous Suzuki couplings of 5-bromo-thiophene anchored to PEG soluble support via a carboxylic function at its C-2 position [116]. Unfortunately, this work was performed in a do-... 

Further examples of functionalization of heterocyclic systems using solid or soluble supports in combination with microwave technology are found in references [52,92,155,190]. 

Bergbreiter DE, Li J (2004) Applications of Catalysts on Soluble Supports. 242 113-176 Bertrand G, Bourissou D (2002) Diphosphorus-Containing Unsaturated Three-Menbered Rings Comparison of Carbon, Nitrogen, and Phosphorus Chemistry. 220 1-25 Betzemeier B, Knochel P (1999) Perfluorinated Solvents - a Novel Reaction Medium in Organic Chemistry. 206 61-78 Bibette J,see SchmittV (2003) 227 195-215... 

Miao, W. Chan, T.H. (2003) Exploration of Ionic Liquids as Soluble Supports for Organic Synthesis. Demonstration with a Suzuki Coupling Reaction. Organic Letters, 5, 5003-5005. 

Stevens, P.D., Li, G.F., Fan, J.D., Yen, M. and Gao, Y. (2005) Recycling of homogeneous Pd catalysts using superparamagnetic nanoparticles as novel soluble supports for Suzuki, Heck, and Sonogashira cross-coupling reactions. Chemical Communications (35), 4435-4437. 

A method for microwave-assisted transesterifications has been described by Van-den Eynde and Rutot [73], The authors investigated the microwave-mediated deriva-tization of poly(styrene-co-allyl alcohol) as a key step in the polymer-assisted synthesis of heterocycles. Several /i-ketoesters were employed in this procedure and multigram quantities of products were obtained when neat mixtures of the reagents in open vessels were subjected to microwave irradiation utilizing a domestic micro-wave oven (Scheme 7.65). The successful derivatization of the polymer was confirmed by IR, 1H NMR, and 13C NMR spectroscopic analyses. The soluble supports... 

Wu and Sun have presented a versatile procedure for the liquid-phase synthesis of 1,2, ,4-tctrahydro-/i-carbolines [77]. After successful esterification of the MeO-PEG-OH utilized with Fmoc-protected tryptophan, one-pot cyclocondensations with various ketones and aldehydes were performed under microwave irradiation (Scheme 7.68). The desired products were released from the soluble support in good yields and high purity. The interest in this particular scaffold is due to the fact that the l,2,3,4-tetrahydro-/f-carboline pharmacophore is known to be an important structural element in several natural alkaloids, and that the template possesses multiple sites for combinatorial modifications. The microwave-assisted liquid-phase protocol furnished purer products than homogeneous protocols and product isolation/ purification was certainly simplified. 

The very first report on the use of ionic liquids as soluble supports was presented by Fraga-Dubreuil and Bazureau in 2001 [102]. The efficacy of a microwave-induced solvent-free Knoevenagel condensation of a formyl group on the ionic liquid (IL) phase with malonate derivatives (E1CH2E2) catalyzed by 2 mol% of piperidine was studied (Scheme 7.89). The progress of the reaction could be easily monitored by 1H and 13C NMR spectroscopy, and the final products could be cleaved from the IL... 

In a recent study, the group of Buijsman presented a microwave-mediated preparation of a different N-imidazolium-based ionic analogue of the well-known AMEBA solid support (Scheme 7.93). With this soluble support, a set of various sulfonamides and amides was prepared, and furthermore the use of this novel linker in the synthesis of a potent analogue of the antiplatelet drug tirofiban was presented [106]. 

A prerequisite for the application of filtration methods is a significant difference in molecular size of the catalyst and the reactants / products. Molecular enlargement, i.e. binding the homogeneous catalyst to soluble supports, is often the method of choice. These supports can be dendrimers, hyper-branched polymers or even simple polymers, giving the opportunity to tailor the support according to the given process. 

The use of such an oxazaborolidine system in a continuously operated membrane reactor was demonstrated by Kragl et /. 58] Various oxazaborolidine catalysts were prepared with polystyrene-based soluble supports. The catalysts were tested in a deadend setup (paragraph 4.2.1) for the reduction of ketones. These experiments showed higher ee s than batch experiments in which the ketone was added in one portion. The ee s vary from 84% for the reduction of propiophenone to up to >99% for the reduction of L-tetralone. The catalyst showed only a slight deactivation under the reaction conditions. The TTON could be increased from 10 for the monomeric system to 560 for the polymer-bound catalyst. 

This cycloaddition has found application in the combinatorial synthesis of indolizines on solid support <1999TL8741 2005BML453> and on soluble support as poly(ethyleneglycol) <2004SL1231>. 

Many other linkers besides those listed above have been developed for two-phase synthesis of oligosaccharides on insoluble supports, and it can be expected that at least some of them will be tested on soluble supports. It should be kept in mind that MPEG-supported syntheses can be easily scaled up therefore, any relationship between both types of polymer supports will be cooperative rather than mutually exclusive. Such linkers will most probably include dialkyl- or diaryl-silyl linkers,10,41 3 and linkers cleavable by photolysis such as the o-nitrobenzyl group and its modifications.44 16... 

A stochiometric approach was applied by Van Koten and co-workers [29], who used chiral carbosilane dendrimers as soluble supports in the in situ ester enolate-imine condensation in the synthesis of /Mactams (e.g. 19, Scheme 20). The formation of the /Mactam products proceeded with high trans selectivity, and with the same level of stereoinduction as was earlier established in reactions without the dendritic supports, (i.e. the use of the enantiopure dendritic support did not affect the enantioselectivity of the C-C bond formation). After the reaction, the dendrimer species could be separated from the product by precipitation or GPC techniques and reused again. 

The International Union of Pure and Applied Chemistry (lUPAC) defines linker as a bifunctional chemical moiety attaching a compound to a solid support or soluble support which can be cleaved to release compounds from the support. A careful choice of the linker allows cleavage to be performed under appropriate conditions compatible with the stability of the compound and assay method [19]. 

Traditionally, soluble polymers have received less attention as polymeric supports than their insoluble counterparts. A perceived problem with the use of soluble polymers rested in the ability to isolate the polymer from all other reaction components. Yet, in practice this separation is not difficult and several methods have capitalized on the macromolecular properties of the soluble support to achieve product separation in liquid-phase synthesis. Most frequently the homogeneous... 

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