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/MeOCH₂CH₂NMe₂ (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, [(R₂NLi)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, [(R₂NLi)(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, [(R₂NLi)₂(epoxide)(ligand)]^⧧, and (2) 2-cycloocten-1-ol derived from both a monomer-based transition structure, [(R₂NLi)(epoxide)(ligand)]^⧧, and a dimer-based transition structure, [(R₂NLi)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.