Lithium Hexamethyldisilazide-Mediated Enolization of Acylated Oxazolidinones: Solvent, Cosolvent, and Isotope Effects on Competing Monomer- and Dimer-Based Pathways

Abstract

Lithium hexamethyldisilazide (LiHMDS)-mediated enolization of (+)-4-benzyl-3-propionyl-2-oxazolidinone in THF–hydrocarbon mixtures shows 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. Even under conditions in which the LiHMDS monomer was the dominant observable form, dimer-based metalation was significant. The mechanism-dependent isotope and cosolvent effects are discussed in the context of ground state stabilization and transition-state tunneling.

Lithium Amino Alkoxide–Evans Enolate Mixed Aggregates: Aldol Addition with Matched and Mismatched Stereocontrol

“…Of course, 2:2 mixed tetramer ( S )- 15a is necessarily unsolvated in toluene, 28 and studies with THF suggested that ( S )- 15a does not accept coordinating solvents either. Using a control experiment of increasing importance in our laboratory, we added pyridine to toluene solutions to probe lithium ion solvation.…”

Lithium Hexamethyldisilazide-Mediated Enolization of Highly Substituted Aryl Ketones: Structural and Mechanistic Basis of the E/Z Selectivities

“…If the reaction had proceeded via a single mechanism involving disolvated monomer (AS 2 ), such as transition structure 5 , a maximum in the plot at intermediate THF concentrations would have been observed. 20 That the rates continue rising even as trisolvated monomer becomes dominant demands that an even more highly solvated form be involved in the enolization. By monitoring the THF-dependent E/Z selectivities over the analogous range of THF concentrations, we separated the components of the two pathways and showed that they contribute to second- and third-order dependencies (see Figure 4, curves A and B, respectively).…”

“…Using toluene in place of hexane resulted in no measurable difference in the THF dependence, which seems self-evident except that pronounced hydrocarbon effects on LiHMDS/THF-mediated enolizations have been observed. 20 …”

Case for Lithium Tetramethylpiperidide-Mediated Ortholithiations: Reactivity and Mechanisms

“…Only recently did we begin to address the challenges of the influence of multiple reactants on observable rate behavior. 29 …”

“…If, for example, “AS” is the reactive form, driving the reactant to AS 2 by using a high solvent concentration will inhibit the metalation. 29 $$1∕2{\mathrm{normalA}}_2{\mathrm{normalS}}_2\begin{array}{c}\hfill \stackrel{K_{\text{eq}}}{\stackrel{2em \rightharpoonup }{2em\leftharpoondown }}\hfill \end{array}[\mathrm{A}\mathrm{S}]\begin{array}{c}\hfill \stackrel{{K^{\prime }}_{\text{eq}}\left[\mathrm{normalS}\right]}{\stackrel{2em\rightharpoonup }{2em \leftharpoondown }}\hfill \end{array}{\mathrm{AS}}_2$$…”