Microwave chemistry and solid-phase organic synthesis

Microwave chemistry and solid-phase organic synthesis 

In this context, microwave-enhanced organic synthesis has attracted a substantial amoLint of attention in recent years since its beginning in 19868,9. As shown by the ever growing amount of publications and number of review articles available on 

For example, many microwave-assisted solid-phase coupling reactions utilise l-methyl-2-pyrrolidone (NMP) or 1,2-dichlorobenzene (DCB) as the reaction solvent. 

Due to their mode of preparation, polymeric resin beads consist of a macroporous internal structure and of highly cross linked areas ( 5%), respectively. The latter renders rigidity to the resin, whereas the porous areas provide a large internal surface for functionalisation, even in the dry state. These macroporous polystyrene-based resins are subsequently modified in various manners, which renders the accessibility to numerous 

One has to note, however, that other polymer composite materials also popular in solid-phase synthesis, for example, polyethylene or polypropylene tea bags such as IRORI kans, lanterns, crowns, or plugs are generally less suitable for high-temperature reactions ( 160°C). Therefore, microwave irradiation is not typically a very suitable tool to speed up reactions, which utilise these materials as either a solid support or as containment for the solid support. 

Microwave Chemistry and Solid-phase Organic Synthesis 

Parallel to these developments in solid-phase synthesis and combinatorial chemistry, microwave-enhanced organic synthesis has attracted much attention in recent years. As is evident from the other chapters in this book and the comprehensive reviews available on this subject [5, 6], high-speed microwave-assisted synthesis has been applied successfully in many fields of synthetic organic chemistry. Any technique which can speed the process of rather time-consuming solid-phase synthesis is of substantial interest, particularly in research laboratories involved in high-throughput synthesis. 

A recent development in this context is the Liberty System introduced by CEM in 2004. This instrument is an automated microwave peptide synthesizer, equipped with special vessels, suitable for unattended synthesis of up to 12 peptides employing 25 different amino acids. For details on solid-phase peptide synthesis refer to Chapter 19. 

In addition, several articles on microwave-assisted parallel synthesis have described irradiation of 96-well filter-bottom polypropylene plates in conventional household microwave ovens for high-throughput synthesis [16-19]. One interesting article described the construction and use of a parallel polypropylene reactor comprising cylindrical, expandable reaction vessels with porous frits at the bottom [20]. This work presented the very first description of reaction vessels for microwave-assisted synthesis that may be useful for performing solid-phase synthesis using bottom-filtration techniques in conjunction with microwave heating. 

For general solid-phase reactions in a dedicated multimode instrument, an adaptable filtration unit is available from Anton Paar (Fig. 16.3). This tool is connected to the appropriate reaction vessel by a simple screw cap and, after turning over the vessel, the resin is filtered by applying a slight pressure up to 5 bar. The resin can then be used for further reaction sequences or cleavage steps in the same reaction vessel without loss of material. At the time of writing, however, no applications of this system for solid-phase synthesis had been reported. 

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Microwave Chemistry and Solid-Phase Organic Synthesis 292... 

In the 1990s the technique of solid-phase organic synthesis (SPOS) became generally popular, but especially in the medicinal chemistry community, for lead detection and lead optimization via combinatorial techniques. The combination with microwave irradiation brought an elegant solution for the problem of the notoriously slower reactions compared to those in solution phase. 

One of the cornerstones of combinatorial synthesis has been the development of solid-phase organic synthesis (SPOS) based on the original Merrifield method for peptide preparation [19]. Because transformations on insoluble polymer supports should enable chemical reactions to be driven to completion and enable simple product purification by filtration, combinatorial chemistry has been primarily performed by SPOS [19-23], Nonetheless, solid-phase synthesis has several shortcomings, because of the nature of heterogeneous reaction conditions. Nonlinear kinetic behavior, slow reaction, solvation problems, and degradation of the polymer support, because of the long reactions, are some of the problems typically experienced in SPOS. It is, therefore, not surprising that the first applications of microwave-assisted solid-phase synthesis were reported as early 1992 [24],... 

Recent advances in the use of Lawesson s reagent include its application in microwave assisted solvent-free syntheses, solid-phase synthesis and combinatorial chemistry.165 Despite the ubiquity of Lawesson s reagent for organic thionation reactions, there are still some classes of compounds that it does not... 

Additionally, for comparison purposes, all steps in the solid-phase protocol (linking, cycloaddition, cleavage) were carried out both under thermal and controlled microwave heating conditions. In general, significant rate enhancements were found for each step and it has been demonstrated that microwave mediation could be combined with the efforts of solid-supported chemistry to enable the development of novel pathways in organic synthesis. 

In this chapter we discuss the new speeding-up techniques, optimized during the last decade, such as solid-phase extraction, polymer-assisted solution-phase synthesis, microwave-assisted organic synthesis, and flow chemistry. The improvements obtained with these techniques are not limited to a subset of chemical reactions (e.g., the reported examples), but they are fully applicable to the entire set of chemistry involved in the synthetic drug discovery process. 

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