Revealing the Role of Solvent in <i>anti</i>-Oxypalladation-Triggered Regiocontrolled Domino Reactions for the Synthesis of Benzazepine- and Tetrahydroquinoline-Containing Scaffolds: A Combined Computational and Experimental Study

Palladium-catalyzed regiocontrolled intramolecular oxypalladation-initiated cascades of multifunctional internal alkyne bearing an <i>N</i>-tosyl tether deliver functionalized benzazepine as an exclusive product via 6-<i>endo-dig</i> pathway in 1,4-dioxane solvent and tetrahydroquinoline scaffold as a major product via the 5-<i>exo-dig</i> pathway in the DMSO solvent. The role of the solvent in controlling the regioselectivity is still unknown which can be a major hurdle for further reaction development. Moreover, the reaction in DMSO suffered from having a mixture of products, and no exclusive formation of tetrahydroquinoline was achieved. Herein, we report a concerted computational and experimental study, revealing the role of the solvent in controlling the reaction outcome. DFT study revealed that the formation of the σ-vinylpalladium intermediate is reversible for the 5-<i>exo-dig</i> pathway while it is irreversible for the 6-<i>endo-dig</i> mechanism in 1,4-dioxane and consequently, the 5-<i>exo-dig</i> pathway is difficult to proceed. In contrast, both the 5-<i>exo-dig</i> and 6-<i>endo-dig</i> pathways are irreversible in DMSO. We predicted an exclusive formation of isobenzofuranone-fused chromane via the 5<i>-exo-dig</i> pathway when the <i>N</i>-tosyl tether is replaced by the <i>O</i>-tether in the internal alkyne in DMSO. The experimental study confirms the theoretical hypothesis and provides a highly chemo-divergent approach for the synthesis of biologically significant chromane with a large substrate scope and up to 95% yield at room temperature.