UC Irvine

This work focuses on the use of N-tosylhydrazones derived from α,β-unsaturated aldehydes – precursors to vinylcarbene ligands – in palladium-catalyzed carbenylative cross-coupling and carbenylative amination reactions. These carbenylative reactions were used to form η3-allylpalladium intermediates that generate stereogenic centers at the carbene center. An initial acyclic model system was used to intercept a well-known prochiral 1,3-diphenylallyl intermediate to probe the feasibility of enantioselectivity in a palladium-catalyzed carbenylative reaction as a proof of concept for asymmetric carbenylation. Following the proof of concept, the substrate scope was expanded to include aliphatic vinyl hydrazones in order to install prenyl functional groups. Conditions to form isoindolines and tetrahydroisoquinolines, present in many natural products, were developed by employing amine-tethered aryl iodides. The isoindoline model system established that kinetic 5-membered ring formation is preferred over thermodynamic 7-membered ring formation and that under our reaction conditions the cyclization is not reversible. Use of N-tosylhydrazones that generate unsymmetrical η3-allylpalladium intermediates that cannot racemize through η3-η1-η3 isomerization provided evidence consistent with migratory insertion as the step responsible for enantioselection in the catalytic cycle. Promising ees are demonstrated indicating that selection of the right chiral ligand and reaction conditions could lead to high levels of enantioselection. Finally, formation of 6-membered ring systems proved challenging in comparison to 5-membered and acyclic systems but provided beneficial information about N-tosylhydrazone decomposition rates and reactivity effects seen from ortho-substitution on the aryl iodide. These results provide new insights into the mechanism of asymmetric palladium-catalyzed carbenylative cross-coupling and carbenylative amination and provide a foundation for future method development.