Simple Aza-Conjugate Addition Methodology for the Synthesis of Isoindole Nitrones and 3,4-Dihydroisoquinoline Nitrones

Aryl-aldehydes containing ortho-substituted α,β-unsaturated carboxylic acid derivatives react with hydroxylamine to afford reactive N-hydroxy-carbinolamine intermediates that undergo intramolecular aza-conjugate addition reactions to afford isoindole nitrones and 3,4-dihydroisoquinoline nitrones in good yield. Conditions have been developed to reduce these isoindole nitrones to their corresponding hydrox-ylamine, enamine and amine derivatives. Isoindole nitrones react with dimethyl acetylenedicarboxylate (DMAD) via a [4+2]-cycloaddition/deamination pathway to afford substituted naphthalene derivatives, whilst 3,4-dihydroisoquinoline nitrones react with DMAD via a [1,3]-dipolar cycloaddition pathway to afford tricyclic heteroarenes