In the course of the last two decades our laboratory explored 3,5-dichloro-2(1H)-pyrazinones as interesting starting materials for a gateway to the elaboration of different types of biologically active compounds. This valuable scaffold allows an easy introduction of a wide range of pharmacologically active groups with the ability to address the diverse set of biological targets. Some of the recently developed 2(1H)-pyrazinone-derived molecules show very promising activities as non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) [1], μ-opioid receptor agonists and selective tissue factor VIIa inhibitors.

Recently, our group has developed the microwave-assisted, transition metal-mediated decoration of the 2(1H)-pyrazinone scaffold in solution phase and on solid-support [2].

Here, we want to discuss the application of microwave-assisted transition metal -mediated cross couplings of the 2(1H)-pyrazinone scaffold. We will demonstrate that these reactions³ resulted in significantly improved yields and rates when performed under microwave irradiation with simultaneous cooling. The Cu (II)-mediated Chan-Lam cross coupling and a one-pot Stille reaction will be discussed.

[1]Heeres, J.; de Jonge, M. R.; Koymans, L. M. H.; Daeyaert, F. F. D.; Vinkers, M.; Van Aken, K. J. A.; Arnold, E.; Das, K.; Kilonda, A.; Hoornaert, G. J.; Compernolle, F.; Cegla, M.; Azzam, R. A.; Andries, K.; de Béthune, M.-P.; Azijn, H.; Pauwels, R.; Lewi, P. J.; Janssen, P. A. J. J. Med. Chem. 2005, 48, 1910-1918.

[2] (a) Kaval, N.; Appukkuttan, P.; Van der Eycken, E. The Chemistry of 2(1H)-pyrazinones in Solution and on Solid Support in Microwave-Assisted Synthesis of Heterocycles, Topics in Heterocyclic Chemistry 2006, Volume Ed. E. Van der Eycken, O. Kappe, Springer-Verlag GmbH. (b) Kaval, N.; Dehaen, W.; Van der Eycken, E. J. Comb. Chem. 2005, 7, 90-95. (c) Kaval, N.; Ermolat'ev, D.; Appukkuttan, P.; Dehaen, W.; Kappe, C. O.; Van der Eycken, E. J. Comb. Chem. 2005, 7, 490-502. (d) Ermolat'ev, D.; Dehaen, W.; Van der Eycken, E. QSAR & Comb. Sci. 2004, 23, 915-918. (e) Kaval, N.; Bisztray, K.; Dehaen, W.; Kappe, C. O.; Van der Eycken, E. Mol. Divers. 2003, 7, 125-133.

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