Studies Dealing with the Cycloaddition/Ring Opening/Elimination Sequence of 2-Amino-Substituted Isobenzofurans<sup>†</sup>

The α-thiocarbocation generated from the Pummerer reaction of an <i>o</i>-amido-substituted sulfoxide is intercepted by the adjacent amido carbonyl group to produce a 2-amino-substituted isobenzofuran as a transient intermediate. In the presence of an electron-deficient dienophile, the reactive isobenzofuran undergoes a Diels−Alder cycloaddition followed by ring opening to furnish a vinylogous <i>C</i>-acyliminium ion that readily aromatizes. The one-pot intramolecular cascade process only occurs either if the olefinic tether is activated by an ester or if a carbonyl group is located adjacent to the nitrogen atom of the 2-amino-substituted isobenzofuran. To examine the amine <i>vs</i> amide influence on the course of intramolecular cycloaddition, density functional theory (DFT) calculations have been carried out for both ground and transition states. The results strongly suggest that the amide-substituted isobenzofurans are destabilized by steric effects between the aromatic ring and the nitrogen-containing side chain. Raising of the ground-state amide energies thereby reduces the activation energy for internal cycloaddition and leads to Diels−Alder adducts more rapidly than for the corresponding amines. Amide tethers emerge as remote-site promoters of intramolecular cycloaddition for tandem processes yielding products with multiple fused rings.