Alkylations of lithium enolates

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 

Typical experimental conditions for reactions of kinetic enolates involve formation of the enolate at very low temperature (-78°C) in THF. Remember, the strong base LDA is used to avoid self-condensation of the carbonyl compound but, while the enolate is forming, there is always a chance that self-condensation will occur. The lower the temperature, the slower the self-condensation reaction, and the fewer by-products there are. Once enolate formation is complete, the electrophile is added (still at -78°C the lithium enolates may not be stable at higher temperatures). The reaction mixture is then usually allowed to warm up to room temperature to speed up the rate of the S 2 alkylation. 

Precisely this sequence was used to methylate the ketone below with LDA acting as base followed by methyl iodide as electrophile. 

In Chapter 17 you saw epoxides acting as electrophiles in Sn2 reactions. They can be used to alkylate enolates providing epoxide opening is assisted by coordination to a Lewis acidic metal ion in this case the lanthanide yttrium(III). The new C-C bond in the product is coloured black. Note that the ketone starting material is unsymmetrical, but has protons only to one side of the carbonyl group, so there is no question over which enolate will form. The base is one of the LDA variants we showed you on p. 668—LHMDS. 

Lewis acid coordinates to 0 and assists ring opening 

Sodium and potassium also give reactive enolates 

Their stability at low temperature means that lithium enolates are usually preferred, but sodium and potassium enolates can also be formed by abstraction of a proton by strong bases. The increased separation of the metal cation from the enolate anion with the larger alkali metals leads to more reactive but less stable enolates. Typical very strong Na and K bases include the hydrides (NaH, KH) or amide anions derived from ammonia (NaNH2, KNH2) or hexamethyldisilazane (NaHMDS, KHMDS). The instability of the enolates means that they are usually made and reacted in a single step, so the base and electrophile need to be compatible. Here are two examples of cyclohexanone alkylation the high reactivity of the potassium enolate is demonstrated by the efficient tetramethylation with excess potassium hydride and methyl iodide. 

The lithium enolates of carboxylic acids can be formed if two equivalents of base are used one to make the carboxylate anion and one to make the enolate. It is not necessary to use a strong base to remove the first proton but, since the second deprotonation requires a strong base such as LDA, it is often convenient to use two equivalents of LDA to form the dianion. With carboxylic acids, even BuLi can be used on occasion because the intermediate lithium carboxylate is much less electrophilic than an aldehyde or a ketone. 

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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 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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