A Quick Synthesis of 1-Arylpyrrolopyrazinones from Linear Alkynylamide Derivatives

Abstract

A rapid synthesis of pyrrolopyrazinone derivatives based on formal double addition across the triple bond of appropriately substituted substrates is presented. The key cyclization step features the formation, mediated by [bis(trifluoroacetoxy)iodo]benzene ­(PIFA), of a 5-aroylpyrrolidinone nucleus from appropriately func­t­ionalized N-protected N-(aminoethyl)amides. After removal of the protecting group, the free amino group is used to accomplish a second heterocyclization process onto the newly formed carbonyl group. By appropriate manipulation of these protecting groups and selection of reaction conditions, a series of pyrrolopyrazinones can be obtained in different stages of hydrogenation.

Key words

hypervalent iodine - alkynylamides - reductive aminations - pyrazinones - bicyclic compounds

References

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8

In previous unpublished results from our group, we found that the presence of free amino and also hydroxy groups is not compatible with the PIFA-assisted intramolecular heterocyclization of unsaturated amides.

14

Additional attempts to hydrogenate unsaturated pyrrolo-pyrazinone 13a to afford 14a resulted in the recovery of the unchanged starting material. Hydrogenation of the imine intermediate J appears to proceed much faster than the isomerization process that would lead to its enamine tautomer.

15

Diastereomers 14 showed a significant NOE between the H1 and H8a protons, indicating that they are located on the same face of the heterocyclic ring.

16

It is known that, in some cases, thiophene-containing olefins can be unreactive under palladium-catalyzed hydrogenation conditions.