Revealing the Role\nof Solvent in <i>anti</i>-Oxypalladation-Triggered Regiocontrolled\nDomino Reactions for the\nSynthesis of Benzazepine- and Tetrahydroquinoline-Containing Scaffolds:\nA Combined Computational and Experimental Study

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