Hemi-Labile Ligands in Organolithium Chemistry:  Rate Studies of the LDA-Mediated α- and β-Metalations of Epoxides

Lithium diisopropylamide (LDA)-mediated α- and β-eliminations of epoxides are described. A comparison between LDA/ n -BuOMe mixtures and LDA/MeOCH 2 CH 2 NMe 2 (LDA/ 3 ) mixtures reveals that the LDA dimer solvated by the “hemi-labile” amino ether 3 imparts dramatic rate accelerations, alters relative efficacies of monomer- and dimer-based metalations, and influences the partitioning between α- and β-metalation. The α-elimination of exo -norbornene oxide by LDA/ n -BuOMe and LDA/ 3 proceeds exclusively via a dimer-based pathway with a transition structure, [(R 2 NLi) 2 (epoxide)(ligand)] ⧧ . The β-elimination of tetramethylethylene oxide by LDA/ n -BuOMe and LDA/ 3 proceeds exclusively via a monomer-based pathway with a transition structure, [(R 2 NLi)(epoxide)(ligand)] ⧧ . cis -Cyclooctene epoxide reacts with LDA/ 3 to give two products: (1) a bicyclooctanol derived from an α-metalation and a dimer-based transition structure, [(R 2 NLi) 2 (epoxide)(ligand)] ⧧, and (2) 2-cycloocten-1-ol derived from both a monomer-based transition structure, [(R 2 NLi)(epoxide)(ligand)] ⧧, and a dimer-based transition structure, [(R 2 NLi) 2 (epoxide)(ligand)] ⧧ . Possible geometries of the transition structures are discussed. Hemi-labile ligands that chelate lithium only at the rate-limiting transition structures maximize both the reaction rates and the mechanistic transparency.