Alkylation, acetoacetic ester

Durst and Liebeskind found that under phase transfer catalytic conditions, in the presence of a catalytic amount of trieaprylylmethylammonium chloride in benzene solution, acetoacetic ester alkylated exclusively on carbon within the limits of detection (see Eq. 15.18) [57]. The solid-liquid phase transfer process utilized in this alkyla-... 

The alkyl halides are also of great importance in synthetic operations (e.g.) using Grigard reagents (p. 280). acetoacetic ester (p. 269) and malonic ester (p. 2- S)-... 

The acetoacetic ester synthesis brings about the overall transformation of an alkyl halide to an alkyl derivative of acetone... 

Section 21 6 The acetoacetic ester synthesis is a procedure in which ethyl acetoac etate is alkylated with an alkyl halide as the first step in the preparation... 

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... 

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

Methylsuccinic acid has been prepared by the pyrolysis of tartaric acid from 1,2-dibromopropane or allyl halides by the action of potassium cyanide followed by hydrolysis by reduction of itaconic, citraconic, and mesaconic acids by hydrolysis of ketovalerolactonecarboxylic acid by decarboxylation of 1,1,2-propane tricarboxylic acid by oxidation of /3-methylcyclo-hexanone by fusion of gamboge with alkali by hydrog. nation and condensation of sodium lactate over nickel oxide from acetoacetic ester by successive alkylation with a methyl halide and a monohaloacetic ester by hydrolysis of oi-methyl-o -oxalosuccinic ester or a-methyl-a -acetosuccinic ester by action of hot, concentrated potassium hydroxide upon methyl-succinaldehyde dioxime from the ammonium salt of a-methyl-butyric acid by oxidation with. hydrogen peroxide from /9-methyllevulinic acid by oxidation with dilute nitric acid or hypobromite from /J-methyladipic acid and from the decomposition products of glyceric acid and pyruvic acid. The method described above is a modification of that of Higginbotham and Lapworth. ... 

Acetoacetic esters react with difluoroamine to give alkyl 3,3-bis(difluoro-amino)butyrates [lOI] (equation 87). 

This reaction sequence is called the acetoacetic ester synthesis. It is a standard procedure for the preparation of ketones from alkyl halides, as the conversion of 1-bromobutane to 2-heptanone illustrates. 

Ethylmalonic Acid.—Like acetoacetic ester (see p. 83), diethylmalonate contains the gioup CO.CHj.CO. By the action of sodium or sodium alroholate, the hydrogen atoms of the methylene group are successively replaceable by sodium. The sodium atoms are in turn replaceable by alkyl or acyl groups. Thus, in the present preparation, ethyl malonic ester is obtained by the action of ethyl iodide on the monosodium compound. If this substance be treated with a second molecule of sodium alcoholate and a second molecule of alkyl iodide, a second radical would be in roduced, and a compound formed of the general formula... 

Just as the malonic ester synthesis converts an alkyl halide into a carboxylic acid, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone having three more carbons. 

Ethyl 3-oxobutanoate, commonly called ethyl acetoacetate or ace tome tic ester, is much like malonic ester in that its ct hydrogens are flanked by two carbonyl groups. It is therefore readily converted into its enolate ion, which can be alkylated by reaction with an alkyl halide. A second alkylation can also be carried out if desired, since acetoacetic ester has two acidic a hydrogens. 

The three-step sequence of 0) enolate ion formation, (2) alkylation, and (3) hydrolvsis/decarboxylation is applicable to all /Tketo esters with acidic a hydrogens, not just to acetoacetic ester itself. For example, cyclic /3-keto esters such as ethyl 2-oxocycIohexanecarboxylate can be alkylated and decarboxy-lated to give 2-substituted cyclohexanones. 

Strategy The acetoacetic ester synthesis yields a methyl ketone by adding three carbons to an alkyl halide. 

What alkyl halides would you use to prepare the following ketones by an acetoacetic ester synthesis ... 

Both the malonic ester synthesis and the acetoacetic ester synthesis are easy to cany out because they involve unusually acidic dicarbonyi compounds. As a result, relatively mild bases such as sodium ethoxide in ethanol as solvent can be used to prepare the necessary enolate ions. Alternatively, however, it s also possible in many cases to directly alkylate the a position of monocarbonyl compounds. A strong, stericaliy hindered base such as LDA is needed so that complete conversion to the enolate ion takes place rather than a nucleophilic addition, and a nonprotic solvent must be used. 

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. 

The cyclic /3-keto ester produced in a Dieckmann cyclization can be further alkylated and decarboxylated by a series of reactions analogous to those used in the acetoacetic ester synthesis (Section 22.7). For example, alkylation and subsequent decarboxylation of ethyl 2-oxocyclohexanecarboxylate yields a 2-alkylcvclohexanone. The overall sequence of (1) Dieckmann cyclization, (2) /3-keto ester alkylation, and (3) decarboxylation is a powerful method for preparing 2-substituted cyclohexanones and cyclopentanones. 

Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide (—CONHCO—) is similar to a /3-keto ester in that the acidic N-H hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to the acetoacetic ester synthesis (Section 22.7). Basic hydrolysis of the N-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7). 

Acetoacetic ester synthesis (Section 22.7) The synthesis of a methyl ketone by alkylation of an alkyl halide, followed by hydrolysis and decarboxylation. 

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... 

Alkylation takes place at the most acidic position of a reagent molecule for example, acetoacetic ester (CH3COCH2COOEt) is alkylated at the methylene and not at the methyl group, because the former is more acidic than the latter and hence gives up its proton to the base. However, if 2 mol of base are used, then not only is the most acidic proton removed but also the second most acidic. Alkylation of this doubly charged anion then takes place at the less acidic position (see p. 458). This technique has been used to alkylate many compounds in the second most acidic position. ... 

Among other methods for the preparation of alkylated ketones are (1) the Stork enamine reaction (12-18), (2) the acetoacetic ester synthesis (10-104), (3) alkylation of p-keto sulfones or sulfoxides (10-104), (4) acylation of CH3SOCH2 followed by reductive cleavage (10-119), (5) treatment of a-halo ketones with lithium dialkyl-copper reagents (10-94), and (6) treatment of a-halo ketones with trialkylboranes (10-109). 

The alkylation of activated halogen compounds is one of several reactions of trialkylboranes developed by Brown (see also 15-16,15-25,18-31-18-40, etc.). These compounds are extremely versatile and can be used for the preparation of many types of compounds. In this reaction, for example, an alkene (through the BR3 prepared from it) can be coupled to a ketone, a nitrile, a carboxylic ester, or a sulfonyl derivative. Note that this is still another indirect way to alkylate a ketone (see 10-105) or a carboxylic acid (see 10-106), and provides an additional alternative to the malonic ester and acetoacetic ester syntheses (10-104). 

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 can be alkylated by isopropyl group if BF3 is saturated at low temperatures in the reaction mixture. 

The esters of nitrous acid are characterised by their high velocities of formation and hydrolysis. They are almost instantaneously decomposed by mineral acids and in the method of preparation given this has been taken into account. The slightest excess of hydrochloric acid must be avoided. Advantage is taken of this property of the alkyl nitrites in all cases where it is desired to liberate nitrous acid in organic solvents (in which metallic nitrites are insoluble). Examples addition of N203 to olefines, preparation of solid diazonium salts (p. 286), production of isonitroso-derivatives from ketones by the action of HN02. This synthesis is often also carried out in the manner of the acetoacetic ester synthesis, with ketone, alkyl nitrite, and sodium ethylate the sodium salt of the isonitrosoketone is formed (cf. in this connexion p. 259) ... 

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. 

Acetoacetic Ester Synthesis The formation of a substituted acetone through the base-catalyzed alkylation or arylation of a (3-keto ester. 

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