Ethoxide, sodium, reaction with ketones

The condensation of aldehydes and ketones with succinic esters in the presence of sodium ethoxide is known as the Stobbe condensation. The reaction with sodium ethoxide is comparatively slow and a httlo reduction of the ketonic compound to the carbinol usually occurs a shorter reaction time and a better yield is generally obtained with the more powerful condensing agent potassium ieri.-butoxide or with sodium hydride. Thus benzophenone condenses with diethyl succinate in the presence of potassium [Pg.919]

An important complement to the Wittig reaction is the reaction of phosphonate carbanions with carbonyl compounds.151 The alkylphosphonate esters are made by the reaction of an alkyl halide, preferably primary, with a phosphite ester. Phosphonate carbanions are more nucleophilic than an analogous ylide, and even when R is a carbanion-stabilizing substituent, they react readily with aldehydes and ketones to give alkenes. Phosphonate carbanions are generated by treating alkylphosphonate esters with bases such as sodium hydride, w-butyllithium, or sodium ethoxide. Alumina coated with KF or KOH has also found use as the base.152... 

Use of ( )-l,4-dibromobut-2-ene in the SIRC reaction gives rise to vinylcyclopropanes (Table 7). The cyclopropanation is induced by bases such as sodium ethoxide, sodium hydride or sodium amide or can be carried out under phase-transfer conditions. The reaction is non-stereoselective however, a diastereomeric excess of 39-80% was obtained with nucleophiles containing a chiral auxiliary. When cyclic ketones are used as nucleophiles, spiro-cyclo-propanes, which serve as precursors for (Z)-jasmonate or methyl jasmonate (Table 7, entries 5-7), are formed. 

After conversion to 19 (70% yield) via Nef reaction and ketalization, selective modification of the terminal olefin by reaction with LAH-TiCl4, quenching with I2, and displacement of the resulting terminal halogen with ethyl acetoacetate anion afforded 20 in 48% overall yield. Deacetylation with sodium ethoxide followed by deketalization under acidic conditions produced an 88% yield of keto ester 21. Seco acid 6 was then obtained (in 29% yield from 18) after reduction of the ketone and ester hydrolysis. Clearly, the significance of this... 

Intermediates that undergo cyclizations of type 94 are probably generated in the reactions of thiazolidines with amines and sulfur, of bis(2-amino-ethyl)disulfide with ketones under acidic conditions, and of 1,2-dithioles with sodium ethoxide. 

The reaction of diethyl oxalate with ketones in the presence of sodium ethoxide, or other bases, has been used extensively examples are given in Scheme 66. Reaction may occur with esterketone ratios of 1 1, 2 1, or 1 2, but only the 1 1 case finds substantial use in modem synthetic practice. Frequently the a-oxalyl ketone is thermally decarbonylated to give the 3-heto ester.An early example of this was provided by Bachmann s synthesis of equilenin. The mechanism of this reaction has teen examined labeling studies showed that it was the ester carbonyl that was eliminated. The intact oxalyl group has teen used as a directing group in steroid methylation while, more recently, 2-oxalylcyclohexanone has provided a route to (R)-(-)-hexahydromandelic acid (Scheme 67). The products of acylation of suitable acyclic ketones can cyclize to form (enolic) cyclopentane-1,2,4-triones (equation 39). ... 

The second classical reaction mentioned above is the acetoacetic ester synthesis. this reaction, an ester of acetoacetic acid (3-oxobutanoic acid) such as ethyl acetoacetate is treated with base under thermodynamic control conditions and alkylated, as with the malonic ester synthesis. Reaction with sodium ethoxide in ethanol (since an ethyl ester is being used) generated the enolate and quenching with benzyl bromide led to 84. Saponification and decarboxylation (as above) gave a substituted ketone (85). Although the malonic ester synthesis and the acetoacetic ester synthesis are fundamentally similar, the different substrates lead to formation of either a highly substituted acid or a ketone. The reaction is not restricted to acetoacetate derivatives, and any p-keto-ester can be used (ethyl 3-oxopentanoate for example). ... 

B.I. The Claisen Condensation. A classical reaction is the condensation of an ester enolate with an ester, illustrated by the self-condensation of ethyl butanoate in the presence of sodium ethoxide to give 3-keto-ester 167. Initial reaction with the base, under thermodynamic control in this case, generates the enolate anion (165). This anion attacks the carbonyl of a second molecule of ethyl butanoate to give 166. Displacement of ethoxide generates ketone 167. As shown here, this reaction is known as the Claisen condensation. A synthetic example is taken from Lubell s synthesis of indolizidine alkaloids, in which diester 168 was treated with LiN(SiMe3)2 in THF at -78°C to give the self-condensation product 169, in 52% yield. 

B.iv. Nitrile Enolates. Nitrile enolates are formed by reaction of a nitrile with LDA or another suitable base. Both alkylation 30 and condensation reactions with aldehydes 3 or ketones are known. 32 in addition to alkyl halides and carbonyl derivatives, condensation can occur with another nitrile. The base-catalyzed condensation of two nitriles to give a cyano-ketone, via an intermediate cyano enolate, is known as the Thorpe reaction. 33.109e Reaction of butanenitrile with sodium ethoxide gave a nitrile enolate, which reacted with a second molecule of butanenitrile at the electrophilic cyano carbon to give 206. Hydrolysis gave an intermediate imine-nitrile (207), which is in equilibrium with the enamine form (208, sec. 9.6.A). Hydrolysis led to the final product of the Thorpe reaction, an a-cyano ketone, 209. 33 Mixed condensations are possible when LDA and kinetic conditions are used to generate the a-lithionitrile (a mixed Thorpe reaction). When pentanenitrile was treated with LDA and condensed with benzonitrile, 2-cyano-l-phenyl-1-pentanone was the isolated product after acid hydrolysis. Nitrile enolates can also be alkylated with a variety of alkyl halides. 34... 

Claisen condensation /kly-zen/ A reaction in which two molecules of ester combine to give a keto-ester - a compound containing a ketone group and an ester group. The reaction is base-catalyzed by sodium ethoxide the reaction of ethyl ethanoate refluxed with sodium ethoxide gives ... 

Michael reaction with an o , S-unsaturated ketone followed by an intramolecular aldol reaction has proven to be a valuable method for the synthesis of 2-cyclohexenones. An especially important example of a Michael-aldol sequence is the Robinson annulation, in which treatment of a cyclic ketone, 8-ketoester, or S-diketone with an a,)8-unsaturated ketone in the presence of a base catalyst forms a cyclohexenone ring fused to the original ring. When the following racemic 8-ketoester, for example, is treated with methyl vinyl ketone in the presence of sodium ethoxide in ethanol, the Michael adduct forms and then, in the presence of sodium ethoxide, undergoes a base-catalyzed intramolecular aldol reaction followed by dehydration to give a racemic substituted cyclohexenone. 

This Reaction should be carefully distinguished from the Claisen Conden-tation, which is the condensation of an ester, under the influence of sodium ethoxide, with (i) another ester, (ii) a ketone, or (iii) a nitrile, with the elimination of alcohol. For details of this condensation, see Ethyl Acetoacetate, p. 264. 

---