Solution-phase synthesis filtrations

An important breakthrough in that respect was the use of soHd-phase organic synthesis (SPOS) where the attachment of the substrate to an insoluble support allowed for easy workup (filtration) and for rapid generation of products via split-mix procedures [1,2]. An important subsequent development consisted of the immobihzation of reagents, scavengers and catalysts. This technique, coined polymer-assisted solution phase chemistry (PASP), allowed solution phase synthesis of compoimds, yet still enjoying the bene-... 

In general, solid-phase synthesis, rather than solution-phase synthesis, can be the preferred method for the generation of combinatorial libraries because of the greater abihty to automate a solid-phase protocol, primarily due to the use of excess reagents in solution to effect cleaner reactions and to the ease of workup by simple filtration. The solid-phase method of peptide synthesis has had many notable successes. However, the preparation of peptides containing more than 20 amino acids in length using the solid-phase technique often causes major problems in that very extensive purification of the final product is needed. 

One research group has exploited the concept of polymer site-isolation in a multistep/one-chamber solution-phase synthesis in which all the reagents, catalysts, and downstream reactants required for a multistep synthesis were combined in one reaction chamber. For instance, a one-chamber/three-step synthesis of substituted acetophenones has been reported (Scheme 10).84 An a-phenethyl alcohol was introduced into a reaction chamber containing the polymer-supported reagents and reactants necessary to accomplish oxidation by polymer-supported pyridinium dichromate 60 bromination by the A-26 perbromide resin 61 and nucleophilic displacement by the A-26 phenoxide resin 62. Filtration afforded the... 

Tripp JA, Stein JA, Svec F, Frechet JMJ, Reactive filtration Use of functionalized porous polymer monoliths as scavengers in solution-phase synthesis, Org. Lett., 2 195-198, 2000. 

The use of polymer-supported reagents (PSRs) [1-4] can combine the benefits of solid-phase chemistry [5-8] with the advantages of solution-phase synthesis, e. g. the simplification of reaction work-up and product isolation. These processes are reduced to simple filtrations (Fig. 1). In addition, PSRs can be used in excess without detriment to the purification step. By using this technique, reactions can be driven to completion more easily than in conventional solution-phase chemistry [9]. 

Parallel organic synthesis can be performed both on a solid phase and in solution. Obviously, solid-phase synthesis is less difficult to automate as work-up usually consists only of simple filtration steps. Solution-phase synthesis often requires automation of work-up procedures such as liquid-liquid extraction or isolation and purification of intermediates. Strategies and devices designed for automating both solution- and solid-phase synthesis are dealt vdth in this chapter. 

In general, liquid/solid extraction methods offer the simplicity of solution phase synthesis and the ease of work-up by simple filtration normally offered by solid phase synthesis. As such, their use will almost certainly become much more widespread in the future. 

Under certain condition, however, reactions are still preferably conducted in solution. This is the case e.g., for heterogeneous reactions and for conversions, which deliver complex product mixtures. In the latter case, further conversion of this mixture on the solid support is not desirable. In these instances, the combination of solution chemistry with polymer-assisted conversions can be an advantageous solution. Polymer-assisted synthesis in solution employs the polymer matrix either as a scavenger or for polymeric reagents. In both cases the virtues of solution phase and solid supported chemistry are ideally combined allowing for the preparation of pure products by filtration of the reactive resin. If several reactive polymers are used sequentially, multi-step syntheses can be conducted in a polymer-supported manner in solution as well. As a further advantage, many reactive polymers can be recycled for multiple use. 

The groups of Giacomelli and Taddei have developed a rapid solution-phase protocol for the synthesis of 1,4,5-trisubstituted pyrazole libraries (Scheme 6.194) [356]. The transformations involved the cyclization of a monosubstituted hydrazine with an enamino-/8-ketoester derived from a /8-ketoester and N,N-dimethylformamide dimethyl acetal (DMFDMA). The sites for molecular diversity in this approach are the substituents on the hydrazine (R3) and on the starting j3-keto ester (R1, R2). Subjecting a solution of the /8-keto ester in DMFDMA as solvent to 5 min of microwave irradiation (domestic oven) led to full and clean conversion to the corresponding enamine. After evaporation of the excess DMFDMA, ethanol was added to the crude reaction mixture followed by 1 equivalent of the hydrazine hydrochloride and 1.5 equivalents of triethylamine base. Further microwave irradiation for 8 min provided - after purification by filtration through a short silica gel column - the desired pyrazoles in >90% purity. 

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