Reversibility and Enantioselectivity of Palladium-Catalyzed Allylic Aminations: Ligand, Base-Additive, and Solvent Effects

The enantioselective, palladium-catalyzed reaction of benzylamine with (<i>E</i>)-1,3-diphenylallyl ethyl carbonate was examined with 12 different chiral ligands across a range of scaffold types. In 8 out of 12 cases, the observed enantiomeric excess was 36-92% higher when DBU or Cs₂CO₃ was added. Nucleophile crossover experiments between the <i>N</i>-benzyl-1,3-diphenylallylamine product and 4-methoxybenzylamine mechanistically linked the changes in enantioselectivity to reformation of the η³-allylpalladium intermediate. In the crossover reactions with 9 out of 12 chiral ligands, 10-75% less elimination to 1-phenylbutadiene was observed with Cs₂CO₃ than with DBU. Analysis of percent crossover vs percent completion of the simultaneous reaction of 1-phenyl-3-methylallyl ethyl carbonate in the crossover experiment revealed that (1) the formation of the 1,3-diphenylallylpalladium intermediate frequently occurred before the reaction of 1-phenyl-3-methylallyl ethyl carbonate was complete, (2) the addition of DBU or Cs₂CO₃ suppressed formation of the 1,3-diphenylallylpalladium intermediate, and (3) the less polar toluene and THF solvents resulted in less or slower formation of the 1,3-diphenylallylpalladium intermediate than the more polar DCM and DMF solvents.