When combinatorial chemistry first emerged, the initial focus was on solid-phase approaches due to the many advantages offered by this technology. Solution chemistry is not regarded as being suitable for combinatorial chemistry, as few reactions lead reliably to very high yields when equimolar amounts of reactants are employed. Thus, reactions in solution are usually followed by tedious isolation and purification procedures. Furthermore, for a specific reaction the difference in reactivity of building blocks becomes more obvious as compared with solid-phase chemistry when applying excesses of reagents. Hence, combinatorial chemistry in solution was centered around easily synthesized compound classes such as amides, sulfonamides, ureas and efficiently prepared heterocycles such as thiazoles. The high-yielding chemistry for the aforementioned substance classes was applied mainly to pharmacophore mapping in which templates of different consecutive reactivity (either rigid or with inherent flexibility) were used for the attachment of pharmacophore groups.
It seemed unlikely that the synthesis of compounds requiring several steps could be performed by combinatorial chemistry in solution. Nevertheless, in recent years a number of technologies have emerged for solution chemistry, so that in many cases this became an alternative to solid-phase synthesis.
Some multicomponent reactions can be carried out very efficiently and are suitable for the synthesis of compound libraries. Among those, the ones in which the final step in the formation of the product is irreversible proceed with high yields.
Often, a sufficient difference in the physical properties between starting material and product can be exploited for easy product purification.Thus, a great difference in pKa values can open up the possibility for an easy purification by ion-exchange resins.
A new area is that of solid phase-supported solution chemistry. This method allows for the application of excesses of reagents to drive reactions to completion. The excess can then be reacted with solid phase-bound functionalities and removed by an ensuing filtration step. Alternatively, intermediates or even final products can be trapped by suitably modified support materials.
Solid phase-bound reagents are another field of polymer-supported solution chemistry which is becoming increasingly important. An example is the use of solid phase-bound tri-phenylphosphine in Wittig-type reactions to avoid the cumbersome separation of the product from the triphenylphosphine oxide that is formed as a byproduct.
Recently, perfluorinated "pony tails" were proposed for the efficient solution synthesis of combinatorial libraries. This approach offers all the advantages of solution chemistry, and yet the compound carrying the fluorous tag can be extracted into a perfluorinated solvent and thus easily separated from other components. More recently, a number of articles have appeared describing this approach in combinatorial synthesis.
2.2 Multicomponent Condensations (MCCs)
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