Ethyl chloroacetate, condensation

This reaction involves the condensation of an aldehyde or ketone with an a-halo ester in the presence of a basic condensing agent (sodium ethoxlde, sodamide, finely divided sodium or potassium iert.-butoxide) to give a glycldio (or ap-epoxy) ester. Thus acetophenone and ethyl chloroacetate yield phenyl-methylglycidic ester (I) ... 

Phenylisoxazolin-5-one condensed with anthranal to give a tricyclic isoxazolylquinoline (Scheme 72) <78CZ264). 3-Methyl-4-phenylazoisoxazoline-5-thione reacted with ethyl chloroacetate for form an intermediate isoxazolethiol, which on heating generated a 1,2,3-triazole (Scheme 73). 

In a 3-I. three-necked, round-bottomed flask fitted with a mechanical stirrer, reflux condenser, and separatory funnel is placed 400 cc. of absolute alcohol (Note i). Through the condenser tube is added slowly, 23 g. (i gram atom) of dean sodium cut into thin slices. The completion of the reaction is hastened by heating the flask on a steam bath. When the sodium has dissolved completely, 143 g. (i.i moles) of ethyl acetoacetate is introduced slowly. Alter starting the mechanical stirrer, 123 g. (i mole) of ethyl chloroacetate (Note 2) is added slowly over a period of an hour, and the reaction mixture is refluxed for five to six hours. At this point the reaction mixture should no longer give an alkaline reaction with moist litmus. 

Much interesting work has been done in the last ten years on the bridging of pyrrole and piperidine rings. Early in their work on this subject Clemo and Metcalfe (1937) prepared quinuclidine (V) by the reduction of 3-ketoquinuclidine (IV), the latter resulting from the hydrolysis and decarboxylation of the product (III) of a Dieckmann internal alkylation, applied to ethyl piperidine-l-acetate-4-carboxylate (II), itself made by condensing ethyl piperidine-4-carboxylate (I) with ethyl chloroacetate. 

The Darzens reaction involves a two-step, base-catalyzed condensation of ethyl chloroacetate with a ketone to yield an epoxy ester. The first step is a carbonyl condensation reaction, and the second step is an SK2 reaction. Write both steps, and show their mechanisms. 

In a i-l. three-necked flask fitted with a stirrer, a thermometer, and an ice-cooled spiral condenser (Org. Syn. Coll. Vol. i, 515) is placed a solution of 98 g. (0.80 mole) of ethyl chloroacetate in 200 cc. of absolute alcohol. The solution is cooled to o° by stirring in a salt-ice bath, and, after the stirrer is stopped, 74 cc. (49 g., 0.83 mole) of trimethylamine, measured after precooling to —5°, is added all at once. The exothermic reaction is controlled sufficiently by cooling so that the temperature of the mixture rises to 6o° in the course of about one hour (Note 1). When there is no longer any heat effect, the mixture is allowed to stand at room temperature for twenty hours (without replenishment of the condenser ice). 

Ethyl benzoylacetate has been prepared by the condensation (by means of sodium ethylate) of ethyl acetate with ethyl benzoate,1 acetophenone with ethyl carbonate,2 and acetophenone with ethyl oxalate, with subsequent heating 3 by treatment of ethyl phenylpropiolate4 or a-bromocinnamic acid 5 with concentrated sulfuric acid, and of ethyl diazoacetate with benzalde-hyde 6 by the condensation of benzene with the monoethyl ester of malonyl monoacid chloride and aluminum chloride,7 of benzoyl chloride with the product of the reaction of magnesium and ethyl chloroacetate in ether,8 of alcohol on benzoylacetimino ethyl... 

Cyclocondensation of 2-aroylbenzoic acid 223 with hydrazine gave the phthalazine derivative 224, which was alkylated with ethyl chloroacetate in aqueous sodium hydroxide or pyridine to give the N-substituted derivative 225. Condensation of the latter with hydrazine afforded the hydra-zide 226, which could be cyclized to give the 2//[l,2,4]triazino[3,4-a]phthalazin-3(4tf)-one 227 (91MI3). 

Quinudidone hydrochloride has been prepared by intramolecular condensation of l-carbethoxymethyl-4-carbethoxypiperidine with potassium 6-8 or, as in the present procedure, with potassium ethoxide.9 l-Carbethoxymethyl-4-carbethoxypiperidine has been prepared by alkylating ethyl hexahydroisonicotinate with ethyl chloroacetate 8 or by the present method.7... 

Concentrated alkali hydroxide decomposes the acetoacetic acid produced by hydrolysis of the ester in a different manner. The cleavage does not take place between the carboxyl group and the rest of the molecule, but between the latter and the —CO.CH3-group, so that two molecules of acetic acid are produced. This acidic hydrolysis introduces a new variation into the synthesis as a whole. The practical importance of this acid hydrolysis may be illustrated by the same example, the condensation product of ethyl acetoacetate with ethyl chloroacetate. 

It is prepared by treating ethyl cinnamate with peracetic acid [212] or by condensation of benzaldehyde with ethyl chloroacetate (in the above Darzens reaction, R = H). The glycidate is used as a long-lasting fragrance material for creating harmonic, fruity notes in household and fine fragrances. 

A. Triethyl a-phtkalimidoethane-a,a, -tricarboxylate. Three hundred and twenty-seven grams (1.0 mole) of diethyl sodium phthalimidomalonate and 735 g. (6.0 moles) of ethyl chloro-acetate (b.p. 144-145°) are placed in a 2-1. Claisen flask fitted with a reflux condenser and rubber stoppers. The mixture is heated under reflux in an oil bath at 150-160° for 2.25 hours. The excess ethyl chloroacetate is removed by distillation at 30 mm. until the heating bath temperature reaches 150° and no more distillate is obtained (Note 1). The brown residual mass is... 

Condensation, of paraldehyde with diethyl malonate, 32, 54 of a-phene thyl chloride with diphenylacetonitrile, 39, 74 of phenylacetylene with ethyl orthoformate, 39, 59 of 1-phenylbiguanide with ethyl chloroacetate, 38,1 of potassium diphenylacetonitrile with benzyl chloride, 39, 73 of potassium trithiocarbonate with potassium chloroacetate, 39, 77 of sodium acetylacetonate to tetraacetylethane, 39, 61 of sodium formylacetone with cyano-acetamide, 32, 32 of tetracyanoethylene with N,N-dimethylaniline, 39, 68 of thiophene, paraldehyde, and hydrogen chloride, 38, 86 of thiourea with furfuryl alcohol, 36,66... 

Heating a mixture of 6,7,8,9-tetrahydro-ll//-pyrido[2,l-b]quinazolin-ll-one (7) and acetyl and benzoyl chlorides, acetic anhydride, and vinyl acetate under reflux gave 6-condensation products (123), whereas reactions with ethyl chloroacetate, ethyl dichloroacetate, and chloral hydrate afforded 6-substituted products (124) (86MI7). 6,7,8,9-Tetrahydro-ll//-pyrido[2,l-b]quinazolin-l 1-one (7) and acetic anhydride, heated under reflux for 36 h, gave compound 123 (X = OAc, R = Me or X = Me, R = OAc, 18%) and its 6-acetyl derivative (124, R = COMe) in 31% yield (87JHC175 91JHC2071). 

B. Danena CmtlenaoHon -OlycHie Eaters The most frequently used method for synthesizing glycidic esters is Darzene condensation, which is based on a discovery in 1SU3 by Ertenmeyer404 that sodium-catalyzed condensation between benz-aldehyde and ethyl -chloroacetate yields tho ct,J -epoxy ester ethyl p-phenylglycidate (Eq. 145). 

Condensation, of 1-phenylbiguanide and ethyl chloroacetate, 38, 1 of sodium formylacetone with cyano-acetamide, 32, 32... 

A three-necked flask with an efficient stirrer and a heated Vigreux column (30 cm) connected to a reflux head with a variable take off and a condenser was charged with a mixture of ethyl chloroacetate (300 g, 2.44 mol), KF (200 g, 3.44 mol) and acetamide (100 g). The mixture was heated with stirring and after 3 min refluxing began the temperature at the head of the column was 117"C. The reaction was maintained at that temperature (2 h) while the crude product was distilled until the temperature gradually fell to 70X. The crude distillate (216 g) was redistilled to give 1 yield 137 g (53%) bp 117-118 C. 

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