Solid-phase organic synthesis Diels-Alder reaction

The Diels-Alder reaction is a [4-1-2]-cycloaddition to synthesize six-membered rings. It is a well-known reaction in combinatorial chemistry and there have been many examples in which this reaction has been described in solid-phase synthesis [266]. In solid-phase organic synthesis it is possible to immobilize the diene (Scheme 3.21) [267] or the dienophile [268]. 

Today, multi-parallel synthesis lies at the forefront of organic and medicinal chemistry, and plays a major role in lead discovery and lead optimization programs in the pharmaceutical industry. The first solid-phase domino reactions were developed by Tietze and coworkers [6] using a domino Knoevenagel/hetero-Diels-Alder and a domino Knoevenagel/ene protocol. Reaction of solid-phase bound 1,3-dicarbonyl compounds such as 10-22 with aldehydes and enol ethers in the presence of piperidinium acetate led to the 1-oxa-1,3-butadiene 10-23, which underwent an intermolecular hetero-Diels-Alder reaction with the enol ethers to give the resin-bound products 10-24. Solvolysis with NaOMe afforded the desired dihydro-pyranes, 10-25 with over 90 % purity. Ene reactions have also been performed in a similar manner [7]. 

Over the last 10 years, a burst of publications and reviews has been focused on the translation of different types of organic reactions towards the solid phase. The difficulty of transferring certain key reactions to the solid phase has stimulated solution phase library synthesis approaches which may be more effective. Cycloaddition reactions allow straightforward and often stereoselective construction of cyclic systems, which can serve as templates for further derivatization. Therefore, cycloaddition reactions play a key role in combinational chemistry sequences. The translation of cycloaddition reactions, especially 1,3-dipolar- [2] and Diels-Alder reactions [3] to the solid phase has been extensively studied. Although the benefits of high pressure for all type of cycloaddition reactions (e.g. [4 + 2] 1,3-dipolar, [2 + 2]) have been very well illustrated in past decades, the application of high pressure to solid phase cycloaddition reactions is still in its infancy. 

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