Nitriles lithium enolate

Amide and imide enolates. Scheme 5.31 illustrates several examples of asymmetric Michael additions of chiral amide and imide enolates. Yamaguchi [163] investigated the addition of amide lithium enolates to -ethyl crotonate, but found no consistent topicity trend for achiral amides. The three chiral amides tested are illustrated in Scheme 5.31a-c. The highest diastereoselectivity found was with the C2-symmetric amide shown in Scheme 5.3Ic. Evans s imides, as their titanium enolates, afforded the results shown in Scheme 5.31d and e [164,165]. The yields and selectivities for the reaction with acrylates and vinyl ketones are excellent, but the reaction is limited to P-unsubstituted Michael acceptors P-substituted esters and nitriles do not react, and 3-substituted enones add with no selectivity [165]. 

The alkylation reactions of enolate anions of both ketones and esters have been extensively utilized in synthesis. Both stable enolates, such as those derived from 6-ketoesters, 6-diketones, and malonate esters, as well as less stable enolates of monofunctional ketones, esters, nitriles, etc., are reactive. Many aspects of the relationships among reactivity, stereochemistry, and mechanism have been clarified. The starting point for the discussion of these reactions is the structure of the enolates. Studies of ketone enolates in solution indicate that both tetrameric and dimeric clusters can exist. THF, a solvent in which many synthetic reactions are performed, favors tetrameric structures for the lithium enolate of isobutyrophenone, for example. ... 

Lithium enolate 329 and a nitrile-furnished enamino ester 330, which on condensation with isocyanates/isothiocyanates gave N-3 substituted 331 (X = O, S) through a tandem nucleophilic addition-intramolecular aza-Michael reaction (Scheme 126) (09JFC1145). 

This reaction has been extended to the Michael Addition on a,)0-unsaturated nitrile by temporarily chelating the Grignard reagent to y-hydroxy unsaturated nitrile. An alternative route involving a free-radical )0-alkylation of nonactivated carbon atoms and subsequent anionic cyclization has been developed as a complementary route of the Robinson annulation. In addition, this reaction has been modified to occur under antibody catalysis" or with the combination of a lithium enolate with aluminum tris(2,6-diphenylphenoxide). Further modifications include the Robinson annulation in supercritical C02, the reaction promoted by K2CO3 under ultrasound,and the solid-supported reaction under microwave irradiation. ... 

The Pd-catalyzed a-allylation of esters was first achieved by the reactions of aUylic carbonates with ketene silyl acetals that can be generated by treating esters with McsSiCl in the presence of a base. The yields of the desired products based on ketene silyl acetals were generally good except in the allylation of lactones (Scheme Selection of solvents is critical since the use of nitriles, such as MeCN and PhCN, leads only to the formation of a,/3-unsaturated esters rather than the a-ally-lated products. Both Reformatsky reagents and lithium enolates of esters have also been successfully a-allylated in the presence of Pd catalysts (Scheme 10). A highly regio- and stereospecific allylation of y-butyrolactone with ( )-2-hexenyl acetate is noteworthy. Since the lithium enolate of esters would react with allylic chlorides even in the absence of a Pd catalyst, however, it is not clear to what extent the reaction is catalyzed by a Pd complex. 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

Another regiospecific preparation of trimethylsilyl enol ethers involves treatment of acyltrimethylsilanes with the lithium anions of alkyl sulfones or nitriles. In this case, the sulfone or nitrile group is eliminated during the silyl alkoxide rearrangement (e.g., 5 — 6). Mixtures of olefin stereoisomers are obtained. Note that 4 and 8 give complementary regiochemical results. 

Quite a number of other electron withdrawing groups containing multiple heteroatomic bonds, such as the ester carbonyl, nitrile, carboxamide, etc., can likewise stabilize carbanions. The lithium salt of tert-butyl acetate 32 is an example of an enolate anion sufficiently stable as a salt to be used as a shelf reagent. Substituents containing easily polarizable atoms, such as sulfur or selenium, are also capable of stabilizing an adjacent anionic center. 

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