Palladium-Catalyzed Isomerization of Aryl-Substituted Epoxides: A Selective Synthesis of Substituted Benzylic Aldehydes and Ketones

Aryl-substituted epoxides bearing multiple methyl substituents on the epoxide ring isomerize in the presence of 5 mol % Pd(OAc) 2 /PR 3 (R = n -Bu, Ph) to form the corresponding benzylic aldehyde or ketone, with complete regioselectivity for the carbonyl compound formed via cleavage of the benzylic C−O bond. No allylic alcohols or products arising from alkyl migration are observed. Rapid reaction rates and nearly quantitative yields are obtained, even with highly sterically hindered epoxides, using tri- n -butylphosphine as ligand and tert -butyl alcohol as solvent. 2-Aryl-substituted epoxides with two methyl substituents on C3 are completely unreactive, consistent with an oxidative addition/β-hydride elimination mechanism. Catalyst variation studies show that both Pd(OAc) 2 and PR 3 are essential for optimal activity and that palladium catalysts formed in this manner are superior to other Pd(0) catalysts (e.g., Pd(PPh 3 ) 4 ). The reactivity of catalytic Pd(OAc) 2 /PR 3 toward multiply-substituted epoxides is compared to traditional Lewis acid catalysts; the former is found to be much more selective for isomerization without skeletal rearrangement. A mechanistic rationale involving turnover-limiting S N 2-like attack of Pd(0) at the benzylic carbon is proposed.