Dialkylamides, enolate formation

E)-Seleclive enolate formation. Corey and Gross (12,285) have noted that (E)-lithium cnolates are formed with high selectivity by treatment of ketones with a lithium dialkylamide followed by trapping with CISi(CH1)3. The (E)-sclectivity may be the effect of LiCI formed on trapping, since the addition of LiCI or LiBr to LiTMP also results in (E)-selective lithium cnolates. The best experimental conditions involve mctalation with crystalline 2,2,6,6-tetramethylpiperidinium bromide, which generates both LiTMP and LiBr under anhydrous conditions. 

Sterically Hindered Base for Enolate Formation. Like other metal dialkylamide bases, sodium bis(trimethylsilyl)amide is sufficiently basic to deprotonate carbonyl-activated carbon acids and is sterically hindered, allowing good initial kinetic vs. thermodynamic deprotonation ratios. The presence of the sodium counterion also allows for subsequent equilibration to the thermodynamically more stable enolate. More recently, this base has been used in the stereoselective generation of enolates for subsequent alkylation or oxidation in asymmetric syntheses. As shown in eq 1, NaHMDS was used to selectively generate a (Z)-enolate alkylation with lodomethane proceeded with excellent diastereoselectivity. In this case, use of the sodium enolate was preferred as it was more reactive than the corresponding lithium enolate at lower temperatures. 

A further improvement utilizes the compatibility of hindered lithium dialkylamides with TMSC1 at —78 °C. Deprotonation of ketones and esters with lithium dialkylamides in the presence of TMSC1 leads to enhanced selectivity (3) for the kinetically generated enolate. Lithium t-octyl-t-butyl-amide (4) appears to be superior to LDA for the regioselective generation of enolates and in the stereoselective formation of (E) enolates. 

In the case of 3-pentanone, evidence has been presented27-28 for thermodynamic control during formation of the (Z)-enolates and for kinetic control during formation of the ( )-eno-lates in the presence or absence of HMPA. Ester enolates are preferentially ( ), when prepared with LDA (THF), and (Z) when prepared with LDA in the presence of HMPA. In contrast, dialkylamides are deprotonated (LDA/THF) preferentially to give the (Z)-enolates. The role of HMPA in the above case is still not quite clear6-29. 

Kinetic enolates. The kinetic enolate of a ketone or ester is generated with enhanced selectivity by a lithium dialkylamide in the presence of chlorotrimethylsilane. In addition, LOBA is superior to LDA for regioseicctivc generation of enolates and for stereoselective formation of (E)-enolatfes. 

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. 

Enol phosphates treated with NaNH2 in liquid ammonia or with lithium dialkylamides give the alkynes in good yields (Scheme 49). Vinyl selenoxides can also be used as a starting material for the preparation of alkynes. Thermolysis at 85-95 C takes place in the presence of DABCO if a syn elimination to the alkyne is possible (Scheme 50). If a syn elimination to an alkyne is blocked by a substituent, allene formation can occur. ... 

Generation of enol silyl ethers from acyclic ketone precursors can be accomplished using the same kind of reagents. Depending on the reaction conditions, stereoselective formation of either the ( )- or the (Z)-isomer of the enol silyl ethers has been reported (Scheme 11). An in situ method of generating the enolate anion with lithium dialkylamides in the presence of trimethylchlorosilane leads to enhanced selection for the kinetically preferred enol silyl ether (e.g. 34a). Lithium r-octyl-r-butylamide (LOBA) is... 

E)-Selective etiolate formation. Ciki lithium enolates are formed with high select dialkylamide followed by trapping with OSit of LiCl formed on trapping, since the addn in (E)-selective lithium enolates. The best with crystalline 2,2,6,6-tetramethylpipcridini and LiBr under anhydrous conditions. 

Trimethylsilylacetate esters may he converted to the enolate by treatment with lithium dialkylamide bases (LDA in Eq. 7.28) in THF at -78°C. These will add to ketones or aldehydes quickly at -78°C, followed by elimination of MOjSiOLi and formation of a,p-unsaturated esters in high yields, uncontaminated by p,y-unsaturated isomers [47]. This is known as the Peterson reaction [48, 49]. The requisite ethyl trimethylsilylacetate is made by the reaction of cldorotrimethylsilane, ethyl bromoacetate, and zinc [50]. Esters of longer-chain acids give mostly 0-silylation under these conditions, but diphenylmethylchlorosilane gives C-silylation selectively. These diphenyl-methylsilylated esters also give the Peterson reaction (Eq. 7.29) [51]. 

Photoinitiation is not the only access to this chemistry, e.g., cathodic induced reduction or the use of alkali metals or other inorganic reducing reagents are also possible, but irradiation often is advantageous for preparative purposes. Since this is a chain process, the use of low-power lamps or a low quantum yield initiation step are not necessarily a limitation. Due to the requirement of a fast cleavage at the radical anion stage, aryl halides are by far the most used reagents, in particular iodides and, to a lower extent, bromides. Nucleophiles are carbanions from sufficiently acidic hydrocarbons, e.g., 1, 3-diphenylindane, fluorene or triphenylmethane [35-37] or, more commonly enolates from ketones [38], esters [39], MA -dialkylamides [40], nitriles [41]. C-C bond formation is obtained also with phenoxide or naphthoxide anions [42,43]. A few representative examples of synthetic applications of the S l... 

To effect P-eliminative oxirane ring openings, lithium dialkylamides are a safer bet than alkyllithiums as the latter may metalate an oxygen-adjacent position instead. The medium-sized six- to ten-membered epoxycycloalkanes are particularly prone to a-metalation and subsequent enolate (after neutralization, cycloalkanone) formation and, on the other hand, insertion into transannular C-H bonds. ... 

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