Alkyl 4 -acetoacetate preparation

Hantzsch dihydropyridine synthesis. The original Hantzsch synthesis2 involves condensation of two equivalents of a keto ester with an aldehyde in the presence of ammonia. In an enantioselective version.5 the chirality is introduced by use of a chiral hydrazone (2) of an alkyl acetoacetate prepared from 1. The anion of 2 is then treated with Michael acceptors to form adducts (3), which cyclize to 4-aryl-l,4-dihydropyridines (4), in 64-72% overall yield and in 84-98% ee. 

The starting semicarbazones were most often prepared directly from the a-keto acids. Godfrin proceeded from a-alkyl acetoacetates, which were converted by oxidation with nitrosylsulfuric acid to a-keto-acid oximes and the latter transformed to semicarbazones or thioseraicarbazones by applying semicarbazide or thiosemicarbazide. For glyoxylic acid semicarbazone a very convenient procedure was employed, making use of the hydrolysis of nonisolated chloral semicarbazone. ... 

This general procedure is effective for the preparation of many types of phenylhydrazones. For example, a substituted diazo compound can be employed.2 Alkylated acetoacetic esters 8 and ethyl benzoylacetate 4 may be used. For the higher homologs, the a-formyl derivatives of ketones may be used in place of ethyl acetoacetate.6 6 Ethyl pyridylacetates may also be substituted for ethyl acetoacetate.7 The products in these cases are the phenylhydrazones of 2-acylpyridines. 

Other mono-alkyl acetoacetic esters may be prepared in an exactly... 

In the preparation of some of the higher mono-alkyl acetoacetic esters the yield is sensibly lowered, owing to the formation of di-alkyl compounds due to secondary reactions of the same type as those described on p. 137. This in like manner can be remedied by using only half the calculated quantity of sodium and alkyl halide. The unattacked acetoacetic ester is recovered by distillation. 

Fig. 13.26. Acetoacetic ester synthesis of methyl ketones I preparation of an alkylated acetoacetic ester.

Ester-substituted ketone enolates are stabilized, and these enolates can be alkylated (acetoacetic ester synthesis). Alkylation is, however, also possible for enolates that are not stabilized. In the case of the stabilized enolates, the alkylated ketones are formed in two or three steps, while the nonstabilized enolates afford the alkylated ketones in one step. However, the preparation of nonstabilized ketone enolates requires more aggressive reagents than the ones employed in the acetoacetic ester synthesis. 

An alternative to the azide synthesis is the Gabriel amine synthesis, which uses a phthalimide alkylation for preparing a primary amine from an alkyl halide. Imides (-CONHCO-) are similar to ethyl acetoacetate in that... 

As with diazo ketones, an a-diazo ester (126) can be prepared by nitrosation of the corresponding a-amino acid (125) or a derivative (equation 51). Alternatively, an a-diazo ester (128) can be prepared by diazo transfer to an alkylated acetoacetate (127), with concomitant deacylation (equation 52). ... 

Enders, MUller and Demir showed that metallated chiral alkyl acetoacetate hydrazones could be used to generate select 1,4-dihydropyridine derivatives in modest yields with high enantioselectivities." For example, treatment of SADP-hydrazone 246, prepared from the condensation of alkyl acetoacetates and 5-(-)-1 -amino-2-(dimethylmethoxymethyl)pyrrolidine... 

Alfrey-Price Q and e-values, 304, 307, 309, 310, 314, 334, 337, 342, 352, 353, 389, 393-395, 400, 416, 419, 424 MA monomer, 247, 272 Alkali cyanide, addition to fumarates, 64 Alkenyl benzyl ethers, MA copolymerization, 532 Alkenylsuccinic anhydride applications, 147, 175 double bond migration, 174 hydrolysis, 175 isomerization catalysts, 174 MA polymerization, 342 MA-olefin adducts, 147-151, 163-165, 172, 173 Alkoxysuccinic acids, preparation, 46 Alkyd resins, MA applications, 44, 479, 499 Alkyl acetoacetates... 

Routes 1-6 can also be used for the preparation of a broad range of carbon-14-labeled /8-keto esters and acids by replacing [ C]acetyl chloride with other acyl chlorides. Alternatively, higher homologs can be prepared by alkylation of doubly deprotonated alkyl acetoacetates (see Section 6.4.1)... 

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. 

Ethyl acetoacetate may also be subjected to double alkylation Show how you could prepare 3 methyl 2 butanone by double alkylation of ethyl acetoacetate ... 

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

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

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. 

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. ... 

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. 

It s reasonable to ask why one would prepare a ketone by way of a keto ester (ethyl acetoacetate, for example) rather than by direct alkylation of the enolate of a ketone. One reason is that the monoalkylation of ketones via their enolates is a difficult reaction to cany out in good yield. (Remember, however, that acylation of ketone enolates as described in Section 21.4 is achieved readily.) A second reason is that the delocalized enolates of (3-keto esters, being far- less basic than ketone enolates, give a higher substitution-elimination ratio when they react with alkyl halides. This can be quite important in those syntheses in which the alkyl halide is expensive or difficult to obtain. 

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... 

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. 

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). 

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... 

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). 

The following substrates were obtained from commercial sources, methyl pyruvate (1), methyl acetoacetate (2), methyl 4-oxopentanoate (1), and methyl 3-oxopentanoate ( ). Alkyl 5-oxohexanoates (4, 5 and 6) were prepared by condensation of methyl acetoacetate and methyl acrylate followed by acidic hydrolysis, decarboxylation, and esterification [8]. Methyl 3-oxo-4-methylpentanoate... 

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