Malonate esters acylation

ETHYL BUTYL ESTER, 37, 34 METHYLENE-, DIETHYL ESTER, 38, 22 Malonic ester, acylation by o-nitro-benzoyl chloride, 30, 70 ethoxymagnesium derivative, solution of, 30, 70 37, 20 Malonic ester syntheses, 30, 7 Malononitrile, 37, S3 Malonyl dichloride, 33, 20 Mandelic acid, 36, 3 -bromo-, 35, 11... 

The malonic ester synthesis might seem like an arcane technique that only an organic chemist would use. Still, it is much like the method that cells use to synthesize the long-chain fatty acids found in fats, oils, waxes, and cell membranes. Figure 22-4 outlines the steps that take place in the lengthening of a fatty acid chain by two carbon atoms at a time. The growing acid derivative (acyl-CoA) is activated as its thioester with coenzyme A (structure on page 1027). A malonic ester acylation adds two of the three carbons of malonic acid (as malonyl-CoA), with the third carbon lost in the decarboxylation. A )8-ketoester results. Reduction of the ketone, followed by dehydration and reduction of... 

Diethyl aminomalonate is a useful intermediate, lending itself to N-acylation the N-acyl derivatives may be alkylated by procedures as established for syntheses via malonic ester. 

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... 

The Gould-Jacobs reaction is a sequence of the following reactions (1) condensation of an arylamine 1 with either alkoxy methylenemalonic ester or acyl malonic ester 2 providing the anilidomethylenemalonic ester 3 (2) cyclization of 3 to the 4-hydroxy-3-carboalkoxyquinoline 4 (3) saponification to form acid 5, and (4) decarboxylation to give the 4-hydroxyquinoline 6. All steps of this process will be described herein with emphasis on the formation of intermediates like 3 and 4. 

Acyl imidazolides are more reactive than esters but not as reactive as acyl halides. Entry 7 is an example of formation of a (3-ketoesters by reaction of magnesium enolate monoalkyl malonate ester by an imidazolide. Acyl imidazolides also are used for acylation of ester enolates and nitromethane anion, as illustrated by Entries 8, 9, and 10. (V-Methoxy-lV-methylamides are also useful for acylation of ester enolates. 

Malonic ester synthesis, 7 acylation by o-nitrobenzoyl chloride, 70... 

A general convenient alkyl methyl ketone synthesis, which utilises the /7-keto ester system as an intermediate, involves the acylation of a malonate ester by way of the ethoxymagnesium derivative. Hydrolysis and decarboxylation to the ketone is accomplished by heating in acid solution the synthesis of cyclohexyl methyl ketone is the illustrative example (Expt 5.96). 

Malonic ester, ethoxymagnesium derivative, solution of, 30, 70 Malonic ester synthesis, 30, 7 acylation by o-nitrobenzoyl chloride, 30, 70... 

Aminothiazole, with acetaldehyde, 42 to 2-mercaptothiazoie, 370 4-Aminothiazole-2,5-diphenyl, to 2,5 di-phenyl-A-2-thiazoline-4-one, 421 Ammothiazoie-A -oxide, 118 2-Aminothiazoles. 12 acidity of, 90 and acrylophenone, 42 acylations of, with acetic acid. 53 with acetic anhydride, 52 with acyl halides, 48 with chloracetyl chloride, 49 with-y-chlorobutyrylchloride, 50 with 0-chloropropionylchloride, 50 with esters, 53 with ethy acrylate, 54 with indoiyl derivatives, 48 with malonic esters, 55 with malonyl chloride, 49 with oxalyl chloride, 50 with sodium acetate, 52 with unsaturated acyl chloride, 49 additions to double bonds, 40 with aldehydes, 98 alkylations, with alcohols, 38 with benzyhydryl chloride, 34 with benzyl chloride, 80 with chloracetic acid, 33 with chloracetic esters, 33 with 2-chloropropionic acid, 32 with dialkylaminoalkyl halides, 33 with dimethylaminoethylchloride, 35 with ethylene oxide, 34, 38... 

When malonic esters are the acylating agents, further reaction may occur with an excess of 2-aminothiazole. yielding 118 (Scheme 79) (278). 

Many alkylation and acylation reactions are most effective using anions of /3-dicarbonyl compounds that can be completely deprotonated and converted to their enolate ions by common bases such as alkoxide ions. The malonic ester synthesis and the acetoacetic ester synthesis use the enhanced acidity of the a protons in malonic ester and acetoacetic ester to accomplish alkylations and acylations that are difficult or impossible with simple esters. 

In contrast, /3-dicarbonyl compounds such as malonic ester and acetoacetic ester are more acidic than alcohols. They are completely deprotonated by alkoxides, and the resulting enolates are easily alkylated and acylated. At the end of the synthesis, one of the carbonyl groups can be removed by decarboxylation, leaving a compound that is difficult or impossible to make by direct alkylation or acylation of a simple ester. 

The malonic ester synthesis makes substituted derivatives of acetic acid. Malonic ester (diethyl malonate) is alkylated or acylated on the more acidic carbon that is a to both carbonyl groups, and the resulting derivative is hydrolyzed and allowed to decarboxylate. 

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