Malonic ester, acetyl-, reaction with

With active methylene compounds, the carbanion substitutes for the hydroxyl group of aHyl alcohol (17,20). Reaction of aHyl alcohol with acetylacetone at 85°C for 3 h yields 70% monoaHyl compound and 26% diaHyl compound. Malonic acid ester in which the hydrogen atom of its active methylene is substituted by A/-acetyl, undergoes the same substitution reaction with aHyl alcohol and subsequendy yields a-amino acid by decarboxylation (21). 

Tosylation of 1146 gave 1147, which was converted to the iodo derivative, whose reaction with the sodium salt of guanine, followed by acetylation to aid its purification and then deprotection, gave 1148 (86JMC1384). The hydroxymethyl groups on C-5 of barbituric acid were introduced starting with malonic ester and then reaction with urea (93MI12). 

Yet a further increase in potency is observed when the para-isobutyl group is replaced by a benzene ring. One published synthesis for that compound is quite analogous to the malonate route to the parent drug. The acetyl biphenyl (50-1) is thus converted to the corresponding arylacetic acid by reaction with sulfur and morpholine, followed by hydrolysis of the first-obtained thiomorpholide. This is then esterified and converted to malonate anion (50-2) with sodium ethoxide and ethyl formate. The anion is quenched with methyl iodide hydrolysis of the esters followed by decarboxylation yields the NSAID flubiprofen (50-3) [51]. 

Acylaminomalonic esters and related reagents are widely used for the synthesis of a-amino acids. The method differs from those syntheses already discussed in that the amino group is incorporated into the system from the outset. A popular reagent is diethyl acetamidomalonate (35). The acetamido group can readily be introduced into the reactive methylene position in diethyl malonate by first converting the latter into the hydroxy-imino derivative (33) by reaction with nitrous acid or an alkyl nitrite (cf. Section 4.2.7, p. 413). This derivative is then reduced catalytically to diethyl aminomalonate (34) which is acetylated using acetic anhydride. 

A condensation occurs between 5-hydroxymethylfurfural and malonic ester20 and in a similar way, two molecules of malonic ester react with furan 2,5-dialdehyde.88 A condensation product, XXXV, has also been obtained with hydantoin.89 5-Hydroxymethylfurfural and its acetyl derivative undergo the Perkin reaction with sodium acetate and acetic anhydride giving 5-acetoxymethylfuran 2-acrylic acid (XXXVI).70 Similar products of the same reaction are obtained from 5-methyl-furfural71 and 5,5 -diformyl-l,l -furylmethyl ether (XXVII).61,72... 

Three methods for the conversion of 3-chlorocarbonyl-1,2,5-thiadiazole (81) to ketones were investigated by Gill. The Lund procedure for the malonic ester synthesis of ketones proved quite successful for the preparation of 3-acetyl-1,2,5-thiadiazole (83). Condensation of 81 with diethyl ethoxymagnesiomalonate provides the ketodiester (82) which undergoes acid hydrolysis and decarboxylation to 83 in 90 % yield. The same reaction sequence employing the sodio derivative of malonic ester was much less efficient. 

Z)-2-butenylene dicarbonate with dimethyl malonate gives a low yield (20—40%) of 2-vinylcyclopropane-l,l-dicarboxylate with up to 70% ee (Scheme 2-38) [54], Reaction with methyl acetoacetate or acetylacetone takes place in a different manner to give a dihydrofuran derivative (59% ee), which results from nucleophilic attack of enolate oxygen at the cyclization step, (c) Asymmetric elimination of an acetyl-acetate ester gives (R)-4-rerr-butyl-l-vinylcyclohexene of up to 44% ee (Scheme 2-39) [55]. (d) Palladium-catalyzed allylic silylation is also applied to asymmetric synthesis... 

The reactions of perfluoroisobutene with sodium salts of malonic esters are difficult to control, owing to rearrangement and base catalysed cyclization, but when the complex BFs NEts is used as HF acceptor, condensation is readily controlled (see Scheme 15 and p. 99) and yields of up to 50% of allene (39) obtained. Antimony pentaliuoride catalyses the electrophilic addition of acid fluorides to 1,1-difluoro- and trifluoro-ethylene. Propiophenones, PhCO CHX-CFs (X = H or F), are obtained from benzoyl fluoride, but with acetyl fluoride, further condensation occurs, and trifluoroethylene yields the jS-diketone, CF3-CHF-CO-CH2Ac. ... 

The reaction of 2-amino-3-nitrosopyridines with compounds containing an activated methylene group permits unambiguous synthesis of various derivatives of pyrido[2,3-b]pyrazine. For example, the pyridine 58 reacts in the presence of sodium ethoxide with a variety of arylacetonitriles and cyanoacetic acid derivatives to provide various 2-substituted 3-amino compounds (59). " " Diethyl malonate reacts similarly to give the 2-carboxylic acid 60, its ester being presumably hydrolyzed in the alkaline reaction conditions. Ethyl acetoacetate yields the 2-acetyl-3-oxo compound 61, and acetylacetone ° provides the 2-acetyl-3-methyl compound 62. The latter condensation proceeds poorly in ethanolic sodium ethoxide, but heating the nitroso compound with acetylacetone under reflux in pyridine gives a 59% yield of the product 62. °... 

Condensation of 3-(2-amino-4-thiazolyl)comnarin 91 with a-acetyl-y-butyrolactone in a mixture of polyphosphoric acid and POCI3 afforded thiazolo[3,2-a]pyrimidin-5-one 92, while condensation of 91 with P-keto esters gave 7-methyl-3 -(2-oxo-2H-chromen-3 -yl)-5 H-[ 1,3]thiazolo [3,2 -a]pyrimidin-5 -ones 93(Scheme 42). Reaction between 91 and diethyl 2-(methoxymethylene)malonate imder solvent-free conditions yielded 3-(2-oxo-2H-chromen-3-yl)-5-oxo-5H[l,3]thiazolo[3,2-a]pyrimidine-6-carboxylate 94 [67],... 

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