An Exploratory Study on Microwave-Assisted Solid-Phase Diels-Alder Reactions of 2(1H)-Pyrazinones: the Elaboration of a New Tailor-Made Acid-Labile Linker Nadya Kaval, † Johan Van der Eycken, ‡ Ju ¨rgen Caroen, ‡ Wim Dehaen, † Gernot A. Strohmeier, § C. Oliver Kappe, § and Erik Van der Eycken* ,† Laboratory for Organic Synthesis, Department of Chemistry, UniVersity of LeuVen, Celestijnenlaan 200F, B-3001 LeuVen, Belgium, Laboratory for Organic and Bio-organic Synthesis, Ghent UniVersity, Krijgslaan 281 (S.4), B-9000 Gent, Belgium, and Institute of Chemistry, Karl-Franzens-UniVersity Graz, Heinrichstrasse 28, A-8010 Graz, Austria ReceiVed January 27, 2003 Microwave-assisted solid-phase Diels-Alder cycloaddition reactions of 2(1H)-pyrazinones with dienophiles are discussed. Separation of the resulting pyridines from the pyridinone byproducts was achieved by applying a traceless-linking concept, whereby the pyridinones remain on the solid support with concomitant release of the pyridine products to solution. As a model study, Wang linker was mimicked in solution using a 4-methoxybenzyl group at the N1 position of the 2(1H)-pyrazinone. The sequence was successfully carried out in solution under conventional thermal heating conditions as well as utilizing high-speed microwave irradiation. The results were adapted to polystyrene supports, using various different acid labile linkers, such as Wang resin, HMPB-AM resin, and a novel, tailor-made acid-labile linker based on syringaldehyde, which has been proven in terms of cleavage rates to be superior to both the standard Wang and HMPB-AM linkers. All steps in the solid-phase protocol (linking, cycloaddition, cleavage) were carried out under both thermal and controlled microwave irradiation conditions. In general, significant rate enhancements were found for reactions carried out under high-temperature microwave conditions, reducing reaction times from hours or days to minutes. Introduction In the course of the last two decades, our laboratory has explored 3,5-dichloro-2(1H)-pyrazinones as interesting start- ing materials for the elaboration of different types of skeletons of biologically active compounds. 1 A versatile synthesis for these scaffolds has been developed starting from suitable aldehyde and amine building blocks, which upon consecutive treatment with cyanide and oxalyl chloride furnish the desired 2(1H)-pyrazinones in moderate to good yields (Scheme 1). 2 This approach allows a wide variation of the substitution pattern of the pyrazinones at the N1- and the C6-position. Various substituents can easily be introduced at the C3-position upon addition/elimination reactions in- volving the sensitive imidoyl chloride moiety. 1 In addition, we have demonstrated that the Stille cross-coupling proce- dure constitutes a very mild method to introduce different alkyl and aryl groups at the 3-position. 3,4 The multifunc- tionalized 2-azadiene system of these heterocycles was used in cycloaddition reactions with electron-rich and electron- poor dienophiles. They easily undergo inter- and intramo- lecular cycloaddition-elimination reaction with acetylenes (Scheme 1), generating for example, pyridines and pyridi- nones (ratio dependent on the substitution pattern of the starting 2(1H)-pyrazinone), 5 R-carbolines and -carbolin- ones, 6 (benzo)furo/pyranopyridines and -pyridinones, 7 pyr- rolopyridin(on)es and naphthyridin(on)es. 4 Many of these heterocycles represent interesting core structures for the synthesis of biologically active compounds as, for example, Substance P antagonists. Upon inter- or intramolecular cycloaddition reaction with alkenes, bicyclic compounds are obtained that have been shown to be valuable building blocks for the synthesis of, for example, -turn mimics 8 and the tricyclic core skeleton of the brevianamide class of natural products. 9 Therefore, it is apparent that the application of a solid- phase approach to the diverse and rich 2(1H)-pyrazinone chemistry outlined above would allow us to take full advantage of combinatorial principles, paving the way for the generation of libraries of many biologically interesting structures. Upon Diels-Alder reaction of a resin-linked 2(1H)-pyrazinone 1 with an acetylenic dienophile (Scheme 2), a labile bicyclic adduct 2 would be formed, which could not be isolated 5 and would directly undergo retro-Diels- Alder fragmentation, yielding pyridine 3 upon loss of the resin-linked isocyanate, providing the resin-bound 2(1H)- pyridinone 4 upon loss of cyanogen chloride, or both. In comparison with the synthesis in solution, two advantages emerge. From the point of view of the generated pyridine, we are dealing with the concept of “traceless-linking”, * To whom correspondence should be addressed. Phone +32 16327406. Fax: +32 16327990. E-mail: erik.vandereycken@chem.kuleuven.ac.be. † University of Leuven. ‡ Ghent University. § Karl-Franzens-University Graz. 560 J. Comb. Chem. 2003, 5, 560-568 10.1021/cc0300098 CCC: $25.00 © 2003 American Chemical Society Published on Web 06/07/2003