Alkylation of lithium enolates

The methyl y-oxoalkanoates shown are not available by alternative methods with similar efficiency and flexibility. Although the reaction of enamines with alkyl ot-bromoacetates proceeds well in some cases, yields are only moderate in many examples.8 A further drawback is that the methods for enamine generation lack the high degree of selectivity and mildness that is characteristic of the preparation of silyl enol ethers. Related alkylations of lithium enolates often afford low yields or polyalkylated products, and are in general very inefficient when aldehydes are utilized as the starting materials.9... 

The reaction of these lithium enolates with alkyl halides is one of the most important C-C bondforming reactions in chemistry. Alkylation of lithium enolates Works with both acyclic and cyclic ketones as well as with acyclic and cyclic esters (lactones). The general mechanism is shown below, alkylation of an ester enolate alkylation of a ketone enolate... 

The enantioselective versions of the alkylation of lithium enolates rely on the complex-ation of the cation by a chiral ligand, which can be in stoichiometric or sub-stoichiometric (catalytic) amounts. 

High diastereoselecivities are normally observed in the alkylation of five-membered ring enolates (eqnations 7 and 8), implying that the alkylation is mainly controlled by steric factors. Thus, with 3-substituted cyclopentanones formation of only the frawi-product (23 and 25, respectively) is preferred. Representative examples are the alkylations of lithium enolates derived from ketones 22 and 24 . Before the electrophiles were added, the enolate solutions were stirred at higher temperature for a longer time to secure the... 

In an extension of this methodology, it has been demonstrated that in some cases the enantioselective alkylation of lithium enolates can be achieved by means of a catalytic amount of 1. As in the stoichiometric version (vide supra), the reaction conditions play a crucial role in determining the yield and % ee. One fundamental modification in the catalytic version is the addition of two equiv of an achiral bidentate amine [e.g. tetramethylethylenediamine (TMEDA) or Al,lV,7V, A -tetramethy-Ipropylene diamine (TMPDA)] to trap the large excess of lithium bromide present at the beginning of the reaction. This catalytic asymmetric variant is illustrated by the reaction of the lithium enolate of 1-tetralone with a variety of electrophiles (eq 7). In this example, the optimal reaction conditions were determined to be 0.05 equiv of 1,2.0 equiv of TMPDA, and 10.0 equiv of the alkyl halide. 

Angular alkylations of lithium enolates of hydrindanones with carbonyl groups in the five- or six-membered rin yield cw-fused products with almost complete stereoselectivity. The lithium enolate of bicyclo [2.2.1]heptan-2-one undergoes exo alkylation with very high stereoselectivity. The presence of a syn methyl group at C-7 reduces the preference for exo alkylation, but it is still preferred over endo alkylation by about 3 1 unless a 5,6-double bond is also present then, endo attack is preferred. The expected steric effects control the stereochemistry of alkylation of other bridged bicyclic systems. - ... 

Direct alkylation of lithium enolates of esters9 62 and lactones 73, via the lithium enolates 71 and 74, with alkyl halides is usually successful. 

Alkylations of lithium enolates of ketones in the presence of chiral bases has been widely studied [77, 559, 1008], but disappointing results were often obtained. However, Koga and coworkers performed asymmetric alkylations of cyclohexanone and tetralone lithium enolates in toluene at low temperatures [108, 1017]. The enolates are generated from the Li amide of chiral diamine 2.4 (X = CH2. R = MeOCH2CH2OCH2CH2). The presence of LiBr is essential to observe a high enantioselectivity (Figure 5.8), and the involvment of mixed aggregates is implied. 

Scheme 3.25. Enantioselective alkylation of lithium enolate/secondary amine/lithium bromide complexes by interligand asymmetric induction [148,149].

Alkylation of lithium enolates is a useful method for synthesis. 

Bis(dibenzylideneacetonato)palladium in conjunction with l,2-bis(diphenyl-phosphino)ethane is a superior catalyst for the alkylation of lithium enolates with allylic acetates. Bis(pentan-2,4-dionato)palladium will catalyse the alkylation of pentan-2,4-dione by allylic alcohols, but the reaction is of limited value in its present form since the catalyst has been shown to cause rearrangements and disproportionation of allylic alcohols. ... 

Related Y(OTf)3-catalyzed alkylations of lithium enolates with epoxides and a one-pot synthesis of 1,2,4-oxadiazole derivatives from yttrium-derived enolates have been reported. ... 

Further methods for the synthesis of optically active amino acids have appeared. A new, general route involves asymmetric alkylation of lithium enolates derived from a chiral SchifT s base of glycine (Scheme 56). Yields, both material and optical, are in the order of 70% furthermore, the chiral reagent, 2-hydroxy-... 

Asymmetric allylic alkylations of lithium enolates of various alkyl aryl ketones 25 were studied by the group of Hou [18] using ferrocene-based chiral ligands. 

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