Mixed aggregates, lithium enolates

Mixed aggregates of chiral lithium amide and lithium ester enolate have been employed in the enantioselective conjugate addition on a,/S-unsaturated esters.27 Michael adducts have been obtained in ees up to 76% combining a lithium enolate and a chiral 3-aminopyrrolidine lithium amide. The sense of the induction has been found to be determined by both the relative configuration of the stereogenic centres borne by the amide and the solvent. 

It is not known whether lithium enolates exist in solution as homoaggregates or as mixed aggregates, nor is it known whether lithium enolates react as aggregates or via other species that might be present in low concentration. But it is certain that... 

After the proton transfer completion, the enolates tend to merge in (1 1) mixed aggregates with the excess lithium amide34. These species have so far been the object of relatively little attention48. Then, as the enolization proceeds to completion, the aggregated enolates form at the expense of the mixed dimers. Another aspect to be considered is the interaction between the lithium enolate and the amine released after protonation of the amide49. This phenomenon will be discussed in the section dedicated to the enantios-elective reactions of enolates. 

Taking the solvation into account in such models is both very difficult and necessary for the best possible understanding of these exceedingly complex phenomena. The disolvation of the amides dimer (one solvent per lithium in THF, THF + HMPA or THF + DMPU)50 seems to be indicated, while trisolvated dimers appear relatively unstable. However, a very extensive semiempirical theoretical (MNDO) study on the various cyclic and open mixed aggregates formed by LDA and LiTMP with LiCl or three different enolates, solvated by discrete molecules of THF or HMPA, showed that general conclusions are almost impossible to draw48. A complex interplay of steric effects, induced by the partners of the aggregate and the solvent, seems to be the dominant influence on the relative stabilities of the species characterized. 

The structure of mixed aggregates involving ester enolates is also of major interest to macromolecular chemists, since ionic additives are often introduced in the polymerization medium. The more stable arrangement between lithium 2-methoxyethoxide and MIB lithium enolate was thus calculated (at the DFT level) to be a 5 1 hexagonal complex with similar O—Li lateral coordinations212. The same team has recently extended this study to complexes formed between the same enolate in THF and a-ligands such as TMEDA, DME, 12-crown-4 and cryptand-2,1,1213. Only in the case of the latter ligand could a separate ion pair [(MIB-Li-MIB),2 THF]-, Li(2,l,l)+ be found as stable, still at the DFT level, as the THF solvated dimer [(MIB-Li)2,4 THF]. 

SCHEME 59. Various types of solid-state mixed aggregates involving ketone lithium enolates (A) pinacolone enolate/lithium amide [LiHMDS/CH2C(OLi)Bu-i, 2 DME]230 (B) pentan-3-one enolate/2 chiral lithium amide232 (C) pinacolone enolate/lithium amide/LiBr [LiHMDS/2 Cl HCtOI.ijBu-f/LiBr, 2 TMEDA]235... 

In the presence of HMPA, 1 1 dimers were observed with both lithium cyclohexenolate or 2,4-dimethylpentanolate and [6Li,15N]LDA or [6Li,15N]LiTMP297. The /S-aminoester enolate presented above (Scheme 60B) was also shown to provide a 1 1 mixed aggregate with LiHMDS in THF288. 

We end this section with the mixed aggregates formed between lithium enolates and enolates of other metals such as zinc or magnesium. These have been obtained by addition of ZnBr2 or MgBr2 to the lithium enolate of 2,2-dimethylpentan-3-one and characterized by 13C NMR and infrared spectroscopies298. The influence of this different type of mixed aggregation on the reactivity has also been studied299. 

Pratt and Streitwieser performed ab initio (HF/6-31G and HF/6-311-FG ) calculations to examine the formation of mixed dimer and trimer aggregates between the lithium enolate of acetaldehyde (lithium vinyloxide, LiOVi) and lithium chloride, lithium bromide and lithium amides. Gas-phase calculations showed that in the absence of solvation effects, the mixed trimer (LiOVi)2 LiX (20) was the most favored species. 

The stereoselective enolization of 3-pentanone by LiTMP mixed aggregates with butyl-lithium was studied by Pratt and coworkers. The mixed aggregate resulted in a slightly higher stereoselectivity, which increased with decreasing amount of the lithium base. Semiempirical PM3 calculations were used in an attempt to determine the mechanism of ketone deprotonation by the mixed aggregate. Equations 20 and 21 show two alternative mechanisms for the formation of lithium acetone enolate in thf solution, involving... 

The nucleophilicity of silyl enol ethers has been examined. Base-induced formation of the enolate anion generally leads to a mixture of (E)- and (Z)-isomers, and dialkyl amide bases are used in most cases. The (EjZ ) stereoselectivity depends on the structure of the lithium dialkylamide base, with the highest EjZ) ratios obtained with LiTMP-butyllithium mixed aggregates in THF. ° The use of LiHMDS resulted in a reversal of the (E/Z) selectivity. In general, metallic (Z) enolates give the syn (or erythro) pair, and this reaction is highly useful for the diastereoselective synthesis of these products. 

The complexity of the solvation of lithium bases has also been demonstrated by studies of LiNPr 2 mediated ester enolization of Bu -cyclohexanecarboxylate in four different solvents (THF, Bu OMe, HMPA/THF and DMPU/THF (DMPU = l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidone)). Even when experiments are designed to exclude mixed aggregate effects, four different mechanisms with nearly identical rates are observed, involving ... 

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