Acetoacetic acid alkylation

Fig. 6. Key intermediates derived from benzene. The alkylation reaction shown employs ethylene oxide. Hydrazine condenses with acetoacetic acid to form...

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. ... 

It is also possible to use the dilithium derivative of acetoacetic acid as the synthetic equivalent of acetone enolate.49 In this case, the hydrolysis step is unnecessary and decarboxylation can be done directly on the alkylation product. 

Acetone cyanohydrin nitrate, a reagent prepared from the nitration of acetone cyanohydrin with acetic anhydride-nitric acid, has been used for the alkaline nitration of alkyl-substituted malonate esters. In these reactions sodium hydride is used to form the carbanions of the malonate esters, which on reaction with acetone cyanohydrin nitrate form the corresponding nitromalonates. The use of a 100 % excess of sodium hydride in these reactions causes the nitromalonates to decompose by decarboxylation to the corresponding a-nitroesters. Alkyl-substituted acetoacetic acid esters behave in a similar way and have been used to synthesize a-nitroesters. Yields of a-nitroesters from both methods average 50-55 %. 

Examples of this approach to the synthesis of ketones and carboxylic acids are presented in Scheme 1.6. In these procedures, an ester group is removed by hydrolysis and decarboxylation after the alkylation step. The malonate and acetoacetate carbanions are the synthetic equivalents of the simpler carbanions lacking the ester substituents. In the preparation of 2-heptanone (entries 1, Schemes 1.5 and 1.6), for example, ethyl acetoacetate functions as the synthetic equivalent of acetone. It is also possible to use the dilithium derivative of acetoacetic acid as the synthetic equivalent of acetone enolate.29 In this case, the hydrolysis step is unnecessary, and decarboxylation can be done directly on the alkylation product. 

Reaction XLIV. (b) Condensation of Alkyl and Aryl Halogen Compounds with the Sodio- and other Metallo-derivatives of Ethyl Aceto-acetate and its Homolognes. (A., 186, 214 201, 143 213, 143.)—Like malonic ester, acetoacetic ester contains two 1 3-carbonyl groups with a methylene group in position 2. It is only to be expected then that it yields with metallic sodium or sodium alcoholate sodio-derivatives from which mono- and di-, alkyl and aryl homologues can be obtained by treatment with a suitable halide, including halogen esters. Acetoacetic acid... 

Fig. 13.27. Acetoacetic ester synthesis of methyl ketones II hydrolysis of the alkylated acetoacetic ester/decarboxylation of the alkylated acetoacetic acid.

In which of the following reactions is an enol, rather than an enolate, the reacting species (a) acetoacetic acid synthesis (b) malonic ester synthesis (c) LDA alkylation (d) Hell-Volhard-Zelinsldi reaction... 

Diastereoselective a-alkylations of acetoacetic acid derivatives <1995T10795> and amino acid aldimines 582 (R = GOG(R )N=GHAr) <1995TL4069> were reported. Tandem Reformatsky and Mannich-type reactions provide an efficient diastereoselective synthesis of /3-amino acids <2006JOG3332>. 

Kryshtal GV, Zhdankina GM, Zlotin SG (2004) Synthesis of derivatives of prenylacetic acids by reactions of alkyl malonate, cyanoacetate, and acetoacetate with alkylating reagents in ionic Hqttids. Russ Chem BuU Int Ed 53(3) 652-658... 

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). ... 

Acetoacetic acid synthesis Synthesis of a. ,. -disubstitutcd methyl ketone by alkylation of a j3-dicarbonyl cotnpound. 

Substituted Methyl Ketones To synthesize a monosubstituted methyl ketone (mono-subsdtuted acetone), we carry out only one alkylation. Then we hydrolyze the monoalkylacetoacetic ester using aqueous sodium or potassium hydroxide. Subsequent acidification of the mixture gives an alkyl-acetoacetic acid, and heating this j8-keto acid to 100 °C brings about decarboxylation (Section 17.10) ... 

A variation of the malonic ester synthetic uses a P-keto ester such as 116. In Section 22.7.1, the Claisen condensation generated P-keto esters via acyl substitution that employed ester enolate anions. When 116 is converted to the enolate anion with NaOEt in ethanol, reaction with benzyl bromide gives the alkylation product 117. When 117 is saponified, the product is P-keto acid 118, and decarboxylation via heating leads to 4-phenyl-2-butanone, 119. This reaction sequence converts a P-keto ester, available from the ester precursors, to a substituted ketone in what is known as the acetoacetic acid synthesis. Both the malonic ester synthesis and the acetoacetic acid synthesis employ enolate alkylation reactions to build larger molecules from smaller ones, and they are quite useful in synthesis. 

When an ester enolate reacts with an aldehyde or a ketone, the product is a hydroxy-ester. This disconnection is shown for both partners. If the reaction is turned around, the reaction of an enolate derived from an aldehyde or a ketone and then with an ester gives a keto-aldehyde or a diketone. Both disconnections are shown. The enolate alkylation reaction involves disconnection of an alkyl halide fragment from an aldehyde, ketone, or ester. In addition, the malonic acid and acetoacetic acid syntheses have unique disconnections. 

In brief, suitable hydrolysis of ethyl acetoacetate derivatives will give mono-or di-alkyl substituted acetones or acetic acids. Tri-substituted acetones or acetic acids cannot be obtained moreover, the di-substituted acetones must... 

It follows therefore that ethyl malonate can be used (just as ethyl aceto- acetate) to prepare any mono or di-substituted acetic acid the limitations are identical, namely the substituents must necessarily be alkyl groups (or aryl-alkyl groups such as CjHjCHj), and tri-substituted acetic acids cannot be prepared. Ethyl malonate undergoes no reaction equivalent to the ketonic hydrolysis of ethyl acetoacetate, and the concentration of the alkali used for the hydrolysis is therefore not important. 

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... 

Transesterification of methyl methacrylate with the appropriate alcohol is often the preferred method of preparing higher alkyl and functional methacrylates. The reaction is driven to completion by the use of excess methyl methacrylate and by removal of the methyl methacrylate—methanol a2eotrope. A variety of catalysts have been used, including acids and bases and transition-metal compounds such as dialkjitin oxides (57), titanium(IV) alkoxides (58), and zirconium acetoacetate (59). The use of the transition-metal catalysts allows reaction under nearly neutral conditions and is therefore more tolerant of sensitive functionality in the ester alcohol moiety. In addition, transition-metal catalysts often exhibit higher selectivities than acidic catalysts, particularly with respect to by-product ether formation. 

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