Azaaldol Condensation of a Lithium Enolate Solvated by <i>N,N,N′,N′</i>-Tetramethylethylenediamine: Dimer-Based 1,2-Addition to Imines

Abstract

The lithium enolate of <i>tert</i>-amylacetate solvated by <i>N,N,N′,N′</i>-tetramethylethylenediamine (TMEDA) is shown to be a doubly chelated dimer. Adding the dimeric enolate to 4-fluorobenzaldehyde-<i>N</i>-phenylimine affords an N-lithiated β-amino ester shown to be monomeric using ⁶Li and ¹⁵N NMR spectroscopies. Rate studies using ¹⁹F NMR spectroscopy reveal reaction orders consistent with a transition structure of stoichiometry [(ROLi)₂(TMEDA)₂(imine)]^⧧. Density functional theory computations explore several possible dimer-based transition structures with monodentate and bidentate coordination of TMEDA. Supporting rate studies using <i>trans-N,N,N′,N′</i>-1,2-tetramethylcyclohexanediamine showing analogous rates and rate law suggest that TMEDA is fully chelated