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Isocyanide based multicomponent reactions (IMCRs) followed by cyclization have become a valuable tools of drug discovery oriented synthetic heterocyclic chemistry since they allow synthesizing diverse nature-like heterocyclic small molecules in simple one-pot procedures. Recently we have developed IMCR of various primary diamines and carbonyl compounds that leads to a wide variety of heterocyclic scaffolds with pyrazine, quinaxoline, hetarenopyrazine, 1,4-diazepine, 1,4-benzodiazepine, and other pharmaceutically relevant cores [1].
Here we report post-condensation modification of the discovered IMCR by involving of dimethyl isocyanoacetal as a bifunctional isocyanide component. This enables further cyclization of intermediate pyrazine-2-amines 4 into target imidazopyrazines 5 under acidic conditions. Since no purification is required for intermediates 4, the entire synthesis can be performed in one-pot mode.
Notably, imidazopyrazine core of general formula 5 is a key structural feature of orexin receptor antagonists (2012), kappa receptor agonists, mGluR5 modulators, and TrkA inhibitors.
Scope of the developed tandem reaction including its expansion for the synthesis of spiro-imidazopyrazines and tetrahydroimidazo[1,2-a][1,4]diazepines as well as its application for small molecule libraries synthesis will be discussed.
[1] Kysil, V. et al. Eur. J. Org. Chem. 2010, 1525–1543.