Evans Enolates: Lithium Hexamethyldisilazide-Mediated Enolization of Acylated Oxazolidinones

Abstract

Lithium hexamethyldisilazide (LiHMDS) is one of the most important bases in organic chemistry due to its prominence as a selective Brönsted base and its high thermal stability. Although the results of numerous crystallographic, spectroscopic, and computational studies have been published, chemists have assiduously avoided mechanistic studies due to the complexity stemming from a shifting dimer–monomer equilibrium of LiHMDS in THF– hydrocarbon mixtures. As part of our research program of oxazolidinone-based enolates, — the so-called Evans enolates that have appeared in more than 1600 patents and countless academic and industrial syntheses— we were drawn to the sequential enolization–aldol addition used by Pfizer that proved challenging during the kilogram scale-up of the hepatitis C drug filibuvir. LiHMDS-mediated enolization of (+)-4-benzyl-3-propionyl-2-oxazolidinone in THF−hydrocarbon mixtures showed unusual sensitivity to the choice of hydrocarbon cosolvent (hexane versus toluene) and to isotopic labeling. Four mechanisms corresponding to monosolvated monomers, trisolvated dimers, octasolvated monomers, and octasolvated dimers were identified by examining and quantitating complex reaction coordinates using FT-IR & NMR spectroscopy, mathematical software, and a unique combination of traditional kinetics with novel numerical integration and computational methods. Even under conditions in which the LiHMDS monomer was the dominant observable form, dimer-based metalation was shown to be significant. The mechanism-dependent isotope and cosolvent effects are discussed in the context of ground-state stabilization and transition-state tunneling. Finally, the LiHMDS mechanistic model developed to describe this complex scenario proves to be general and will enable the exploration of the indisputably important chemistry of LiHMDS and enolates — and many other substrates — to detailed mechanistic analysis