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

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.