Diethyl enolate

Olefin synthesis from a,p-unsaturated ketones. Ireland and Pflster1 have extended the procedure of Kenner and Williams (1,248, ref. 2) for deoxygenation of phenols to conversion of a,/3-unsaturated ketones into olefins. For example, the a,)3-unsaturated ketone (1) was reduced by lithium-ammonia to give an enolate anion which reacted with diethyl phosphorochloridate to give the phosphate ester (2) in 56% yield. This ester was reduced in high yield by lithium in a mixture of ethylamine and r-butanol to the olefin (3). It is noteworthy that only one olefin is formed. Actually the conversion of (1) into (3) can be carried out in 50% yield without isolation of the diethyl enol phosphate. 

The sequence can also be applied to the enolate anion formed by conjugate addition of organometallic reagents to a,/8-unsaturated ketones. Thus addition of diethyl phosphorochloridate to a mixture of A4-cholestene-3-one (4) and dimethyl-copperlithium gives the diethyl enol phosphate (5) in 55% yield. Reduction of the ester gives the olefin (6) in high yield. 

The method is related to that of Fetizon for preparation of A2-steroids by lithium-ammonia reduction of diethyl enol phosphates generated from 2-bromo-3-ketones (see Triethyl phosphite, this volume). 

Diethyl enol phosphate 47 rearranges to p-ketophosphonates 49 upon treatment with LDA.34 This reaction probably proceeds via cleavage with LDA to give an enolate phosphonium ion pair 48 which then interacts to give the anion under equilibrium conditions.34 The reaction mixture is quenched with acetic acid. The enol phosphate 47 is prepared by Perkow reactions from the corresponding a-halocyclohexanone.34... 

Malinowski and Kroczynski have concluded that the 2-carboalkoxy group in a series of dimethyl and diethyl enol phosphates 104 enhance insecticidal activity. The most effective insecticide and acaricide in their series is 105.57... 

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

In a reaction related to the mixed Claisen condensation nonenolizable esters are used as acylatmg agents for ketone enolates Ketones (via their enolates) are converted to p keto esters by reaction with diethyl carbonate... 

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... 

In this reaction the enolate of diethyl malonate adds to the p carbon of methyl vinyl ketone... 

Most of the reactions of ester enolates described so far have centered on stabilized eno lates derived from 1 3 dicarbonyl compounds such as diethyl malonate and ethyl ace toacetate Although the synthetic value of these and related stabilized enolates is clear chemists have long been interested m extending the usefulness of nonstabilized enolates derived from simple esters Consider the deprotonation of an ester as represented by the acid—base reaction... 

Acylation of ketones (Sec tion 21 4) Diethyl carbo nate and diethyl oxalate can be used to acylate ketone enolates to give p keto esters... 

Section 21 7 The malonic ester synthesis is related to the acetoacetic ester synthesis Alkyl halides (RX) are converted to carboxylic acids of the type RCH2COOH by reaction with the enolate ion derived from diethyl mal onate followed by saponification and decarboxylation... 

Section 21 9 Michael addition of the enolate ions derived from ethyl acetoacetate and diethyl malonate provides an alternative method for preparing their a alkyl derivatives... 

Alkyl halides by reaction with the enolate anion derived from diethyl acetamidomalonate... 

Malonic ester synthesis (Section 21 7) Synthetic method for the preparation of carboxylic acids involving alkylation of the enolate of diethyl malonate... 

Dimethyl 2,3-pentadienedioate has also been prepared from the enol phosphate of diethyl acetone-1,3-dicarboxylate. ... 

A carbonyl group cannot be protected as its ethylene ketal during the Birch reduction of an aromatic phenolic ether if one desires to regenerate the ketone and to retain the 1,4-dihydroaromatic system, since an enol ether is hydrolyzed by acid more rapidly than is an ethylene ketal. 1,4-Dihydro-estrone 3-methyl ether is usually prepared by the Birch reduction of estradiol 3-methyl ether followed by Oppenauer oxidation to reform the C-17 carbonyl function. However, the C-17 carbonyl group may be protected as its diethyl ketal and, following a Birch reduction of the A-ring, this ketal function may be hydrolyzed in preference to the 3-enol ether, provided carefully controlled conditions are employed. Conditions for such a selective hydrolysis are illustrated in Procedure 4. 

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. 

Partial control of enolate geometry occurs also when the enol phosphate, prepared by treatment of fluoroalkyl ketones with sodium diethyl phosphite, is... 

Mixed Claisen condensations (Section 21.3) Diethyl carbonate, diethyl oxalate, ethyl formate, and benzoate esters cannot form ester enolates but can act as acylating agents toward other ester enolates. 

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