Ketones, ethyl enolization

The reason why the carbonyl group in -santonin remained intact may be that, after the reduction of the less hindered double bond, the ketone was enolized by lithium amide and was thus protected from further reduction. Indeed, treatment of ethyl l-methyl-2-cyclopentanone-l-carboxylate with lithium diisopropylamide in tetrahydrofuran at — 78° enolized the ketone and prevented its reduction with lithium aluminum hydride and with diisobutyl-alane (DIBAL ). Reduction by these two reagents in tetrahydrofuran at — 78° to —40° or —78° to —20°, respectively, afforded keto alcohols from several keto esters in 46-95% yields. Ketones whose enols are unstable failed to give keto alcohols [1092]. 

D20, 70 and 30% respectively of the axial [23] and equatorial [24] deuteriated ketone were formed. If it is assumed that protonation of the enolate oxygen atom is faster than that of C(c), this result corresponds to the stereoselectivity of axial and equatorial attachment of D+ to the enol (27). The higher selectivity between axial and equatorial deuteriated ketones observed for hydrolysis of the corresponding ethyl enol ether (90 10) and pyrrolidine enamine (>90 10) means that the stereoselectivity is probably smaller for the enol than for the related compounds. 

Enol acetates and corresponding derivatives constitute another class of unsaturated compounds that can advantageously be hydrogenated with high enantiomeric excess. This reaction is related to the enantioselective reduction of ketones. Acylated enol carboxy-lates (as an equivalent of a-keto carboxylic acid) can likewise be successfully reduced with rhodium(I) catalysts based on (5,5)-ethyl-DuPHOS (eq 8). Subsequent deprotection of the hydroxyl group or reduction of the carboxylic acid derivatives so obtained deliver chiral a-hydroxy carboxylates and 1,2-diols, respectively. 

The naturally occurring clerodane diterpenoid ( )-sacacarin has been synthesized by R.B. Grossman and co-workers in only 10 steps using a double annulation of a tethered diacid and 3-butyn-2-one. " The second ring of sacacarin was prepared by an intramoiecuiar Dieckmann condensation of an ester and a methyl ketone in excellent yield. The resulting end was then immediately converted to the corresponding ethyl enol ether using ethanol and an acid catalyst. 

Preparation.—The reaction of triphenylphosphine with 1-bromoalkyl ketones has been described in which the initially formed labile enolic salts (59) are converted irreversibly into phosphonium salts via ion-pairs (Scheme 4). When R is larger than ethyl the ion-pair is not formed and the enol salts decompose in the pr ence of atmospheric moisture to give alkyl aryl ketones. No enol phosphonium salts are isolated from the reaction of bromo-diketones with triphenylphosphine in ether. The phosphonium salts (60) are precipitated directly. 

The addition of ketone-derived enol silanes and aldehydes in the presence of 184 at -78 °C in propionitrile afforded the aldol adducts in excellent yields as well as diastereo- and enantioselectivity (Eq.29) [106]. The versatility of this catalyst is evidenced by the fact that enol silanes derived from aliphatic methyl and ethyl ketones as well as acetophenone are substrates for the aldol addition reaction. 

Once an ester enolate is generated, it can react with another ester in a Claisen condensation however, it may also react with the carbonyl of an aldehyde or ketone. The ester enolate anion is a nucleophile and it reacts with an aldehyde or ketone via acyl addition. Kinetic control conditions are the most suitable for this reaction in order to minimize Claisen condensation of the ester with itself (self-condensation). If ester 74 (ethyl propanoate, in green in the illustration) is treated first with LDA and then with butanal (21, in violet), for example, the initial acyl addition product is 78. The new carbon-carbon bond is marked in blue and treatment with dilute aqueous acid converts the alkoxide to an alcohol in the final product of this sequence, 79. Compound 79 is a P-hydroxy ester, which is the usual product when an ester enolate reacts with an aldehyde or a ketone. Ester enolate anions react with ketones in the same way that they react with aldehydes. 

The synthesis of the 19-nor analog (83) of Sarett s ketone also takes place via nonaromatic intermediates, being carried out in accordance with Scheme 63 [663, 664]. The cyclic diene (77) required for the synthesis was obtained from the ethyl enol ether of 1,3-cyclohexanedione (76) by the Normant reaction and transketalization with ethylmethyldioxolan. Conden-... 

Thus the sodio derivative (I) of the enol form of ethyl acetoacetate is obtained. This mechanism can clearly apply also to the condensation of an ester with a suitable ketone or nitrile, as in the above reactions (ii) and (iii) respectively. 

Esters of nonenolizable monocarboxylic acids such as ethyl benzoate give p diketones on reaction with ketone enolates... 

Stabilized anions exhibit a pronounced tendency to undergo conjugate addition to a p unsaturated carbonyl compounds This reaction called the Michael reaction has been described for anions derived from p diketones m Section 18 13 The enolates of ethyl acetoacetate and diethyl malonate also undergo Michael addition to the p carbon atom of a p unsaturated aldehydes ketones and esters For example... 

Acetoacetic ester synthesis (Section 21 6) A synthetic method for the preparation of ketones in which alkylation of the enolate of ethyl acetoacetate... 

The crude ketal from the Birch reduction is dissolved in a mixture of 700 ml ethyl acetate, 1260 ml absolute ethanol and 31.5 ml water. To this solution is added 198 ml of 0.01 Mp-toluenesulfonic acid in absolute ethanol. (Methanol cannot be substituted for the ethanol nor can denatured ethanol containing methanol be used. In the presence of methanol, the diethyl ketal forms the mixed methyl ethyl ketal at C-17 and this mixed ketal hydrolyzes at a much slower rate than does the diethyl ketal.) The mixture is stirred at room temperature under nitrogen for 10 min and 56 ml of 10% potassium bicarbonate solution is added to neutralize the toluenesulfonic acid. The organic solvents are removed in a rotary vacuum evaporator and water is added as the organic solvents distill. When all of the organic solvents have been distilled, the granular precipitate of 1,4-dihydroestrone 3- methyl ether is collected on a filter and washed well with cold water. The solid is sucked dry and is dissolved in 800 ml of methyl ethyl ketone. To this solution is added 1600 ml of 1 1 methanol-water mixture and the resulting mixture is cooled in an ice bath for 1 hr. The solid is collected, rinsed with cold methanol-water (1 1), air-dried, and finally dried in a vacuum oven at 60° yield, 71.5 g (81 % based on estrone methyl ether actually carried into the Birch reduction as the ketal) mp 139-141°, reported mp 141-141.5°. The material has an enol ether assay of 99%, a residual aromatics content of 0.6% and a 19-norandrost-5(10)-ene-3,17-dione content of 0.5% (from hydrolysis of the 3-enol ether). It contains less than 0.1 % of 17-ol and only a trace of ketal formed by addition of ethanol to the 3-enol ether. 

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