Enolates aggregation

The same approach was used with LiSIBP and LiBnPAT, upon incremental addition of LiHMDS in THF solution, as a potential model for the study of the alkylation of chiral amide-enolate aggregates. From the average values for ATagg (respectively, 560 and 760 M 1) and the values of the ratio LmXed/ (respectively, 100 and 20), the initial alkylation was estimated to involve 40% of monomeric enolate (although it represents less than 1% of the species in solution), a situation unsuitable for asymmetric synthesis (Scheme 83)256. 

There are several examples of the effect of LiX on enolate aggregation leading to increased enantiomeric excess in asymmetric chemical events. Koga and co-workers developed an efficient enantioselective benzylation of the lithium enolate of 19 by using a stoichiometric amount of chiral ligand 22 with LiBr in toluene [50]. The chiral lithium amide 22 was prepared by treatment of a mixture of the corresponding amine 21 and LiBr in toluene with a solution of n-BuLi in hexane. Sequential addition of ketone 19 and benzyl bromide gave rise to 20 in 89 % yield and 92 % ee. The amount... 

Dimethylaminomethylacetophenone (145) reacts with LDA in diethyl ether to produce the tetramoic enolate aggregate (146).This aggregate is an internally chelated variation of the tetramer (137). The origin of this enolate was not well defined in the original paper describing its characterization. 

Scheme 3,1. Equilibrating dimeric and tetrameric enolate aggregates. Formal charges are not shown. There is probably more than one solvent molecule coordinated to the monomers (left) and dimer (middle). In the tetramer (right), the R moiety is deleted from the indicated oxygen (O ) for clarity.

The structurally novel bicyclic oxazinone was prepared based on D-glucopyranose. The lithium enolates of these compounds undergo highly diastereoselective alkylation reactions with reactive alkyl halides, in modest yields. Use of the phosphazene P4 base enhanced the yields of these processes, suggesting that metal enolate aggregation is at least partly... 

One of the general features of the reactivity of enolate anions is the sensitivity of both the reaction rate and the ratio of C- versus O-alkylation to the degree of aggregation of the enolate. For example, addition of HMPA frequently increases the rate of enolate alkylation reactions. Use of dipolar aprotic solvents such as DMF and DMSO in place of the THF also leads to rate acceleration. These effects can be attributed, at least in part, to dissociation of the lithium enolate aggregates. Similar effects are observed when crown ethers or similar cation-complexing agents are added to reaction mixtures. 

Unique H-Li couplings of 0.45 and 0.89 Hz through the Li-N-C-H network have been observed by Willard and co-workers in the spectrum of a chiral enolate aggregate containing a lithium enolate and a chiral lithium amide. This is a second example of such coupling reported in the literature. For the first time scalar coupling of 0.80 Hz between proton and lithium nuclei across the H-C-C-Li path was reported by Gunther and co-workers in 1993.2 ... 

A Structural support for the substantial effects of lithium salts on the formation and reaction of lithium enolates, the LiX effect [la] was also provided by Williard and coworkers in crystal structures of the heterodimers 5a and 5b, the first fully characterized halide/enolate aggregates. They were generated, as shown in Scheme 3.3, from diisopropyl ketone in the presence of TMEDA, and... 

The successive replacement of the enolate by aldolate moieties en route from an enolate tetramer to an aldolate tetramer might involve severe reconstruction of the skeleton. Thus, a mixture of pinacolone, its lithium aldolate with pivalaldehyde, and the enolized aldolate dianion was recently reported to cocrystallize in a 1 1 3 ratio as a heptalithium cage compound missing any cube-shaped unit [15]. Rather complex crystal structures aldolate-enolate aggregates were also found for calcium enolates [8b]. 

Figure 3.5 H-DOSY spectrum of mixed enolate aggregate 4. Copied from Ref. [lib].

This collection of different, partly contradictory answers to the question of the reactive species in an ensemble of enolate and enolate aggregates may reflect the difficulties mechanistic interpretations of enolate reactions encounter clearly there is much we do not understand about lithium reagent aggregate reactivities [33]. 

Scheme 5.42 Visualization of Trost s rationale for the stereochemical outcome in the allyla-tion of an LDA-lithium enolate aggregate (left) and a naked" enolate (right).

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