Ethyl acetoacetate ester

Methyl ethyl acetic acid may be prepared from methyl ethyl malonic ester by hydrolysis and subsequent heating of the methyl ethyl malonic acid.1 The yield by this method, in the preparation of large quantities, is about 61 per cent of the theoretical amount based on the malonic ester used. The acid was first prepared by Saur2 from methyl ethyl acetoacetic ester. It has also been made by oxidation of the corresponding aldehyde with chromic acid.3... 

This Reaction should be carefully distinguished from the Claisen Conden-tation, which is the condensation of an ester, under the influence of sodium ethoxide, with (i) another ester, (ii) a ketone, or (iii) a nitrile, with the elimination of alcohol. For details of this condensation, see Ethyl Acetoacetate, p. 264. 

Thus the sodio derivative (I) of the enol form of ethyl acetoacetate is obtained. This mechanism can clearly apply also to the condensation of an ester with a suitable ketone or nitrile, as in the above reactions (ii) and (iii) respectively. 

Synthetic use of Ethyl Acetoacetate, In view of the great importance of the ester in synthetic work, the following practical points concerning its use should be borne in mind. 

Mono and Di-iubstitution Derivatives. The enolic sodium derivative of ethyl acetoacetate (E) is prepared by mixing ethanolic solutions of the ester and of sodium ethoxide. It should not be prepared by the direct action of metallic sodium on the ester, as the reaction is slow and the nascent hydrogen evolved reduces some of the ester to ethyl p4iydroxy- butyrate, CH3CH(OH)CHjCOOEt. 

In the present preparation, ethyl acetoacetate is treated with sufficient nitrous acid to convert half into the a-nitroso (or a-oximino) ester, which is reduced by zinc and acetic acid to the a-amino ester (I). The latter then condenses with... 

This reaction consists of the condensation of two molecular equivalents of a 1,3 diketone (or a J3-keto-ester) with one equivalent of an aldehyde and one of ammonia. Thus the interaction of ethyl acetoacetate and acetaldehyde and ammonia affords the 1,4-dihy dro-pyridine derivative (1), which when boiled with dilute nitric acid readily undergoes dehydrogenation and aromatisation" to gb e the diethyl ester of collidine (or 2,4,6-trimethyl-pyridine-3,5 dicarboxylic acid (II)). For the initial condensation the solid aldehyde-ammonia can conveniently be used in place of the separate reagents. 

Gently warm a mixture of 32 g. (32 ml.) of ethyl acetoacetate and 10 g. of aldehyde-ammonia in a 400 ml. beaker by direct heating on a gauze, stirring the mixture carefully with a thermometer. As soon as the reaction starts, remove the heating, and replace it when the reaction slackens, but do not allow the temperature of the mixture to exceed 100-no the reaction is rapidly completed. Add to the mixture about twice its volume of 2A -hydrochloric acid, and stir the mass until the deposit either becomes solid or forms a thick paste, according to the quality of the aldehyde-ammonia employed. Decant the aqueous acid layer, repeat the extraction of the deposit with more acid, and again decant the acid, or filter off the deposit if it is solid. Transfer the deposit to a conical flask and recrystallise it twice from ethanol (or methylated spirit) diluted with an equal volume of water. The i,4-dihydro-collidine-3,5-dicarboxylic diethyl ester (I) is obtained as colourless crystals, m.p. 130-131°. Yield 12 5 g,... 

The formation of ethyl acetoacetate is an example of a general reaction knowu as the acetoacetlc ester condensation in which an ester having hydrogen on the a-carbon atom condenses with a second molecule of the same ester or with another ester (which may or may not have hydrogen on the a-carbon atom) in the presence of a basic catalyst (sodium, sodium ethoxide, sodamide, sodium triphenylmethide) to form a p-keto-ester. The mechanism of the reaction may be illustrated by the condensation of ethyl acetate with another molecule of ethyl acetate by means of sodium ethoxide. ... 

The first step is the interaction of the basic catalyst with the ester to produce the carbanion (I) the carbanion so formed then attacks the carbonyl carbon of a second molecule of ester to produce the anion (II), which is converted to ethyl acetoacetate (II) by the ejection of an ethoxide ion. Finally (III) reacts with ethoxide ion to produce acetoacetic ester anion (IV). This and other anions are mesomeric thus (IV) may be written ... 

This is an alternative experiment to the actual preparation of the ester and will give the student practice in conducting a distillation under diminished pressure. Commercial ethyl acetoacetate generally contains inter alia some ethyl acetate and acetic acid these are removed in the following procedure. 

Simple esters (e.g., ethyl acetate) undergo the acetoacetic ester condense tion (compare Section 111,151). The effective condensing agent is sodium ethoxide, produced by the action of sodium upon traces of alcohol present in the ester ... 

The formation of acyloins (a-hydroxyketones of the general formula RCH(OH)COR, where R is an aliphatic residue) proceeds best by reaction between finely-divided sodium (2 atoms) and esters of aliphatic acids (1 mol) in anhydrous ether or in anhydrous benzene with exclusion of oxygen salts of enediols are produced, which are converted by hydrolysis into acyloins. The yield of acetoin from ethyl acetate is low (ca. 23 per cent, in ether) owing to the accompanying acetoacetic ester condensation the latter reaction is favoured when the ester is used as the solvent. Ethyl propionate and ethyl ji-butyrate give yields of 52 per cent, of propionoin and 72 per cent, of butyroin respectively in ether. 

The ester 322A is made by ester exchange with ethyl acetoacetate and a suitable alcohol. The product 322B decarboxylates spontaneously on heating. Draw out the whole sequence starting from ethyl acetoacetate. 

On Irealmenl wilh alkoxide bases esters undergo self condensalion lo give a p kelo ester and an alcohol Elhyl acelale for example undergoes a Claisen condensalion on Ireal menl wilh sodium elhoxide lo give a p kelo ester known by ils common name ethyl ace toacetate (also called acetoacetic ester)... 

Recognize too that the reaction sequence is one that is characteristic of p keto esters in general and not limited to just ethyl acetoacetate and its derivatives Thus... 

The properties of diethyl malonate that make the malonic ester synthesis a useful procedure are the same as those responsible for the synthetic value of ethyl acetoacetate The hydrogens at C 2 of diethyl malonate are relatively acidic and one is readily removed on treatment with sodium ethoxide... 

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... 

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... 

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

Methyl acetoacetate (MAA) and ethyl acetoacetate (EAA) are the most widely used esters they are found ia the pharmaceutical, agricultural, and allied industries. Both esters are used extensively as amine protecting agents ia the manufacture of antibiotics and synthetic sweeteners (Dane Salts) (147). Principal outiets for MAA are the manufacture of the organophosphoms insecticide dia2inon [33341-5] (148,149) and the uracil herbicides bromacil [31440-9] and terbacil [5902-51-2] (150,151) (see Insect conztiol technology Herbicides). 

Conra.d-Limpa.ch-KnorrSynthesis. When a P-keto ester is the carbonyl component of these pathways, two products are possible, and the regiochemistry can be optimized. Aniline reacts with ethyl acetoacetate below 100°C to form 3-anilinocrotonate (14), which is converted to 4-hydroxy-2-methylquinoline [607-67-0] by placing it in a preheated environment at 250°C. If the initial reaction takes place at 160°C, acetoacetanilide (15) forms and can be cyclized with concentrated sulfuric acid to 2-hydroxy-4-methylquinoline [607-66-9] (49). This example of kinetic vs thermodynamic control has been employed in the synthesis of many quinoline derivatives. They are useful as intermediates for the synthesis of chemotherapeutic agents (see Chemotherapeuticsanticancer). 

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