Multicomponent/Palladium-Catalyzed Cascade Entry to Benzopyrrolizidine Derivatives: Synthesis and Antioxidant Evaluation

A versatile and efficient
protocol for the synthesis of highly
substituted benzopyrrolizidines (tetrahydro-3H-pyrrolo­[2,1-a]­isoindol-3-ones) is reported. The strategy consisted of
an Ugi four-component reaction/elimination methodology to afford dehydroalanines
containing trans-cinnamic acid derivatives and different
substituted 2-bromobenzylamines, followed by a palladium-catalyzed
5-exo-trig/5-exo-trig cascade carbocyclization process. Gratifyingly,
benzopyrrolizidines were obtained in moderate to good yields (42–77%)
with a Z geometry due to the structural requirements
for syn-β-hydride elimination. The prepared
heterocyclic scaffolds are decorated with several substituents and
incorporate a benzopyrrolizidine-fused system, along with an embedded
cinnamic acid derivative, two privileged medicinal chemistry scaffolds.
Additionally, since some of the compounds are derived from the well-known
antioxidants ferulic and sinapinic acids, they were tested for their
in vitro antioxidant capacity. The data suggested that compounds having
a p-hydroxyl group showed moderate 2,2-diphenyl-1-picrylhydrazyl-radical-scavenging
activity and were effective antioxidants in preventing lipoperoxidation
in a thiobarbituric acid reactive substances assay.