Alkylation of acetoacetic ester

Methyl-5-hexen-2-one has been prepared by alkylation of acetoacetic ester with methallyl chloride, followed by cleavage the overall yield in the two steps was 51%.2... 

This reaction has been considered above (method 184) with respect to ease of mono- and di-alkylation. A large number of condensing agents have been compared, including sodium and potassium ethoxide, sodium in dioxane or toluene, sodium hydride, sodium amide, and sodium or potassium i-butoxide. In general, sodium ethoxide is recommended in the alkylation of acetoacetic ester with primary halides (73%) potassium ethoxide with branched halides, such as isobutyl and s-butyl halides... 

Alkylation catalyst. In a detailed study of alkylation of acetoacetic esters, Renfrew and Renfrew found potassium t-butoxide in general to be the best base, particularly for alkylation of a-substituted esters. In the Sarett synthesis of cortisone, potassium /-butoxide served well as base for effecting two successive alkylations of the 14-ketone (1). Methylation (CH3I, t-BuOK) gave a single stereoisomer, regarded as... 

Still another possibility in the base-catalyzed reactions of carbonyl compounds is alkylation or similar reaction at the oxygen atom. This is the predominant reaction of phenoxide ion, of course, but for enolates with less resonance stabilization it is exceptional and requires special conditions. Even phenolates react at carbon when the reagent is carbon dioxide, but this may be due merely to the instability of the alternative carbonic half ester. The association of enolate ions with a proton is evidently not very different from the association with metallic cations. Although the equilibrium mixture is about 92 % ketone, the sodium derivative of acetoacetic ester reacts with acetic acid in cold petroleum ether to give the enol. The Perkin ring closure reaction, which depends on C-alkylation, gives the alternative O-alkylation only when it is applied to the synthesis of a four membered ring ... 

Hydroxymethy lene compounds are O-alkylated by potassium carbonate and an alkyl halide in acetone, but these conditions produce only the usual C-alkylation with /J-diketones or keto esters.423 Nitro-compounds have also been reported to give either O- or C-alkylation.424 While acylation of the sodium derivative of acetoacetic ester normally takes place on carbon, O-acylation is the result in pyridine. 

Another formal total synthesis of ( )-yohimbine has been worked out by Wenkert et al. (229) by preparing O-methylhexadehydroyohimbine (420), which was first prepared by Kametani and co-workers (224-226) as a key intermediate toward ( )-yohimbine. In Wenkert s approach, pyridinium salt 427 was y-alkylated with acetoacetic ester anion. The product 428 then underwent intramolecular condensation, affording tetracyclic quinone 429. Methylation of 429... 

Acetoacetic ester synthesis is the preparation of substituted acetones, and it s an important method for creating a variety of products. It begins with the reaction of acetoacetic ester (a dicarbonyl) or a similar compound with a strong base to produce a carbanion, which then reacts with alkyl halide, RX. The structure of acetoacetic ester is in Figure 15-10. Figure 15-11 illustrates an example of an acetoacetic ester synthesis and two possible outcomes. Figure 15-12 shows the preparation of 2-heptanone with a 65 percent yield via the acetoacetic ester synthesis. Figure 15-13 presents the preparation of 2-benzylcyclohexanone with a 77 percent yield. 

The enolate ions of acetoacetic ester and other active methylene compounds react with 0-propiolactone to give the ethoxycarbonyl derivative, but the yields are generally not high. Application of this reaction to 2-ethoxycarbonyldodecanone (equation 53) has been recently patented, with the product reported to be a useful perfume intermediate (77JAP(K)77133952). The reaction is used quite widely with diketene, which gives C-acylation rather than alkylation of the enolate ion, followed by cyclization (72CPB1574). 

Since the terminal methyl group of acetoacetic ester is alkylated, its dianion is reacted with C HjCKjCI. 

The various alkyl derivatives of acetoacetic ester are important, because of the hydrolyses they undergo (see p. 193). Some reference to the structure of the acetoacetic ester will be found under Reaction XLVI., p. 145 further reactions are discussed in Reactions XLVII., LIII. 

Reaction LXVH. (a) Ketonic Hydrolysis of Alkyl Derivatives of Ethyl Acetoacetate. (A., 138, 211.)—This reaction illustrates one of many synthetical uses of acetoacetic ester. When that ester or its mono- or dialkyl derivatives is boiled with dilute aqueous or alcoholic alkalis or baryta water, or sulphuric acid, ketonic hydrolysis occurs, and acetone or its mono- or di-substituted derivatives is formed—... 

The second hydrogen on the methylene unit of acetoacetic ester can also be replaced by an alkyl group, creating a disubstituted acid. To accomplish this conversion, the reaction product in step 2 above would be reacted with a very strong base to create a carbanion. 

The sodium derivative of acetoacetic ester, prepared by treating the ester with an alcoholic solution of sodium ethylate, is converted into an alkyl substituted ester by boiling with any alkyl iodide ... 

Similarly, the a-methylene group of acetoacetic ester is oximinated by the action of sodium nitrite in glacial acetic acid (63%). Nitrosation of alkylated malonic, acetoacetic, and benzoyl acetic esters with subsequent cleavage affords an excellent synthesis for a-oximino esters, RC(=-NOH)COjC2Hj. A survey of several possible procedures for this conversion has been made." If a /3-keto acid is nitrosated, then the Carboxyl group is lost and an a-oximino ketone is formed, viz.,... 

This finding made it easy to carry out the following reaction sequence (i) alkylation at the y-carbon atom of a bis-anion of acetoacetic ester (ii) O-acetylation of the resulting product and (iii) reaction with a cuprate reagent to lead to the substitution of the OAc group by another alkyl group. This route now constitutes one of the most reliable methods to assemble stereoselectively... 

Intermediate formation of a cyclopropyl ring has also been suggested in electrochemical reductions although to a lesser extent. 2-Alkyl-substituted acetoacetic esters undergo the Tafel rearrangement upon reduction at a lead cathode in an acidic medium with complete reduction of the functional groups Analysis of the reduction products... 

The first step is the deprotonation of acetoacetic ester at the C2 position with one equivalent of base. The resulting enolate is nucleophilic and reacts with the electrophilic alkyl halide in an Sn2 reaction to afford the C2 substituted acetoacetic ester, which can be isolated. The ester is hydrolyzed by treatment with aqueous acid to the corresponding p-keto acid, which is thermally unstable and undergoes decarboxylation via a six-membered transition... 

It will be observed that throughout this discussion of carbanions no mention has been made of the intermediate formation of an enol or of enolization. It now seems extremely probable that in reactions such as aldol formation (p. 176), the Claisen condensation (p. 185), acetoacetic or malonic ester reactions (pp. 182, 201), and the halogenation of ketones (pp. 206, 207) the carbanion is the actual reaction intermediate and that the formation of an enol simply represents an alternative non-essential course of reaction for the carbanion. In the alkylation of malonic ester, for example, a carbanion (XXV and XXVI) may be formed by reaction of the neutral ester with ethoxide ion. 

As a typical example, the enol ether of acetoacetic ester 3, when treated with anhydrous crotyl alcohol in hot xylene in the presence of dinitrophenol/potassium hydrogen sulfate (4 1, 2g/100g 3), undergoes transetherification and rearrangement to give a 1 1 mixture of diastereomers of the alkylated /J-oxo ester 4452. 

Oi i Tl acetoacetic ester synthesis. The acetone "core" of the product is shown in the box. This product would require alkylation at BOTH carbons of the acetone "core" of acetoacetic ester, in reality, only one carbon undergoes alkylation in... 

The only difference between the acetoacetic ester synthesis and the malonic ester synthesis is the use of acetoacetic ester rather than malonic ester as the starting material. The difference in starting material causes the product of the acetoacetic ester synthesis to be a methyl ketone rather than a carboxylic acid. The carbonyl group of the methyl ketone and the carbon atoms on either side of it come from acetoacetic ester, and the rest of the ketone comes from the alkyl halide used in the second step of the reaction. 

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