Malonic anhydrides preparation

The anhydrides can be prepared by the action of acetic anhydride on the corresponding malonic acid in the presence of a small amount of sulfuric acid, followed by neutralization of the mineral acid with powdered barium carbonate and evaporation to dryness in a high vacuum. The residual malonic anhydride is then heated to the decomposition point at a low pressure, and the ketene is collected in a cold receiver. This procedure has been applied to the synthesis of low-molecular-weight dialkylketenes (R is methyl, ethyl, f2-propyl, or isopropyl) in 50-80% yields. ... 

A second procedure consists in heating mixed anhydrides prepared from disubstituted malonic acids and diphenylketene. 

A unique preparation of ketenes is by thermal decomposition of malonic anhydrides, which form ketenes and carbon dioxide (Scheme 7.47). Ketene, methylketene, and dimethylketene are formed by this methodology. Surprisingly, the monomethyl malonic anhydride is the most reactive and the dimethyl is the slowest. 

The disubstituted malonic anhydrides can be prepared from the corresponding malonic acids and acetic anhydride in the presence of a little sulfuric acid, with neutralization of the mineral acid by treatment with barium carbonate and removal of acetic acid and acetic anhydride by distillation. The r dual malonic anhydride is decomposed by heating under low pressure. This method appears to have been used only for dimethylketene (80% yield), diethylketene (55% yield), methylethyl-ketene (65% yield), and dipropyl- and diisopropyl-ketenes (50% yields). 

B. From Mixed Anhydrides Prepared from Malonic Adds and Diphenylkdene... 

Reactions. Heating an aqueous solution of malonic acid above 70°C results in its decomposition to acetic acid and carbon dioxide. Malonic acid is a useful tool for synthesizing a-unsaturated carboxyUc acids because of its abiUty to undergo decarboxylation and condensation with aldehydes or ketones at the methylene group. Cinnamic acids are formed from the reaction of malonic acid and benzaldehyde derivatives (1). If aUphatic aldehydes are used acryhc acids result (2). Similarly this facile decarboxylation combined with the condensation with an activated double bond yields a-substituted acetic acid derivatives. For example, 4-thiazohdine acetic acids (2) are readily prepared from 2,5-dihydro-l,3-thiazoles (3). A further feature of malonic acid is that it does not form an anhydride when heated with phosphorous pentoxide [1314-56-3] but rather carbon suboxide [504-64-3] [0=C=C=0], a toxic gas that reacts with water to reform malonic acid. 

Snyder and Smith prepared diethyl acetamidomalonate in 40% yield by reduction of diethyl isonitrosomalonate in ethanol over palladium on charcoal followed by direct acetylation of diethyl aminomalonate in the filtrate with acetic anhydride. Ghosh and Dutta used zinc dust instead of palladium. A modification using Raney nickel is described by Akabori et al. Shaw and Nolan reported a 98% yield by conversion of diethyl oximino-malonate-sodium acetate complex. 

Acetone cyanohydrin nitrate, a reagent prepared from the nitration of acetone cyanohydrin with acetic anhydride-nitric acid, has been used for the alkaline nitration of alkyl-substituted malonate esters. In these reactions sodium hydride is used to form the carbanions of the malonate esters, which on reaction with acetone cyanohydrin nitrate form the corresponding nitromalonates. The use of a 100 % excess of sodium hydride in these reactions causes the nitromalonates to decompose by decarboxylation to the corresponding a-nitroesters. Alkyl-substituted acetoacetic acid esters behave in a similar way and have been used to synthesize a-nitroesters. Yields of a-nitroesters from both methods average 50-55 %. 

Magnesium enolates play an important role in C-acylation reactions. The magnesium enolate of diethyl malonate, for example, can be prepared by reaction with magnesium metal in ethanol. It is soluble in ether and undergoes C-acylation by acid anhydrides and acyl chlorides (entries 1 and 3 in Scheme 2.14). Monoalkyl esters of malonic acid react with Grignard reagents to give a chelated enolate of the malonate monoanion. 

Diethyl ethylidenemalonate has been prepared by heating acetaldehyde, diethyl malonate, and acetic anhydride 2 3 by heating the same reagents plus zinc chloride 4 by treating acetaldehyde and diethyl malonate with sodium ethoxide or piperidine 6 and by heating diethyl malonate, ethylidene bromide, and ethanolic sodium ethoxide.6... 

They are easily prepared from Grignard reagents, magnesium ethoxide or with the complex magnesium chloride-trialkylamine (see Section II where the generation of these reagents is discussed). The acylation of anions derived from malonates can be achieved with acyl chlorides, acyl imidazoles, aUcoxycarbonylimidazoles or mixed anhydrides. 

Barbituric acid may also be prepared by condensing urea with malonyl chloride [75] or with malonic acid in the presence of acetic anhydride [76]. 

This acid is considered to be the trane form largely because of lte Physical properties. Jt is possible that the other form has bssn prepared by Perkin by heating a 1,1,2,3 acid which he prepared from dlbromsuccinlc ester and sodium malonic ester. The acid differed in melting point from the one prepared by Buchner and formed no anhydride. A repetition of Perkin s work by Buchner gave negative results, (over)... 

Malonic acid condenses especially readily. Even at ordinary temperatures, in presence of acetic anhydride, it yields benzalmalonic acid with benzaldehyde. Better results are obtained, however, by using a less powerful condensing agent—glacial acetic acid—at 100°. This synthesis is interesting as providing a method for the preparation of certain monobasic acids, since all malonic acids readily lose carbon dioxide on heating (see Preparation 427). 

Diethyl methylidenemalonate. This reagent (3) polymerizes easily and can be prepared by depolymerization of oligomers, but is more readily available in sufficiently pure form from diethyl malonate (1) by conversion to the Diels-Alder adduct 2 from anthracene, paraformaldehyde, and 1. When heated at 190-200° with maleic anhydride, the adduct 2 decomposes to 3 in an overall yield of -50%. 

Reaction of 3,4-dihydro-7-nitro-2//-l, 4-benzoxazine-4,5-dicarboxylic anhydride with diethyl malonate in the presence of 60% NaH in N, yV-dimethylacetamide at 120°C afforded ethyl 7-hydroxy-9-nitro-5-oxo-2,3-dihydro-5//-pyrido[l,2,3-cte]-l,4-benzoxazine-6-carboxylate (93MIP4). 9-Chloro-2,3-dihydro-7-hydroxy-6-(jV,./V-disubstituted thiocarbamoyl)-5//-pyrido[l,2,3-de]-l,4-benzoxazin-5-ones were prepared from 7-chloro-3,4-dihydro-2//-1,4-benzoxazine-4,5-dicarboxylic anhydride with 3-(N,N-disubstituted amino)-3-thioxopropionates in the presence of 60% NaH in yV,yV-dimethylacetamide (95MIP5). 

Anhydrides—Continued reduction to alcohols, 155 reduction to lactones, 535 Arenes, see Hydrocarbons, aromatic Amdt-Eistert reaction, 433, 487, 573 Aryl esters. Fries rearrangement, 344 hydrolysis, 169 preparation, 169 Aryl halides, see Halides Atyloxy acids, preparation, by aceto-acetic ester synthesis, 430 by malonic ester synthesis, 429 from atyloxy alcohols, 419 from atyloxy cyanides, 414 preparations listed in table 48, 460 Aryloxy acyl halides, preparation, 547 preparations listed in table 61, 553 Aryloxy esters, preparations listed in table 55, 516... 

Olefinic esters may be obtained directly by the Knoevenagel reaction. Alkyl hydrogen malonates are used in place of malonic acid. Decarboxylation then gives the ester directly as in the preparation of ethyl 2-heptenoate (78%) and methyl m-nitrocinnamate (87%). Alkyl hydrogen malonates are readily available by partial hydrolysis of dialkyl malonates. The use of malonic ester in the condensation leads to olefinic diesters, namely, alkylidenemalonates such as ethyl heptylidenemalonate (68%). A small amount of organic acid is added to the amine catalyst since the salts rather than the free amines have been shown to be the catalysts in condensations of this type. Various catalysts have been studied in the preparation of diethyl methylenemalonate. Increased yields are obtained in the presence of copper salts. Trimethylacetalde-hyde and malonic ester are condensed by acetic anhydride and zinc chloride. Acetic anhydride is also used for the condensation of furfural and malonic ester to furfurylidenemalonic ester (82%). ... 

Hydroxymercuri methyl malonic methyl ester, IIOlIg.CMe (C02Me)2.—The preparation is carried out in a similar manner to tlie above, using equal molecules of the ester and mercuric oxide and continuing the shaking for several days. It is a white amorphous solid, insoluble in the usual solvents. When saponified as above it gives an 85 per cent, yield of the anhydride of h droxymercuri-propionic acid. In a similar manner the methyl ester of ethylmalonic acid yields 80 per cent, of hydroxymercuribiityric acid anhydride. 

A mixture of 1000 g. (6.75 moles) of ethyl orthoformate, 1260 g. (12.3 moles) of acetic anhydride, 960 g. (6.0 moles) of ethyl malonate, and 0.5 g. of anhydrous zinc chloride is prepared in a 5-1. three-necked flask equipped with a thermometer, a gas inlet tube, and a 12-in. column packed with Berl Saddles (Note 1). The column is attached to a still head and condenser. The contents of the flask are well agitated for 5 minutes by a stream of dry air and then heated (Note 2) as follows 102-115° for lYi hours, 115-127° for 7 hours [after the eighth hour of heating, 250... 

Ethyl ethoxymethylenemalonate has been prepared by heating ethyl orthoformate, ethyl malonate, and acetic anhydride in the presence of zinc chloride. A higher yield of purer product is obtained by the method described above, which is a modification of the Claisen procedure. 

The mixed anhydride method is analogously and conveniently applied to the preparation of a-amino acids (60) from malonic acid half-esters (59 equations 38 and 39). - ... 

Mixed anhydride synthesis. For use of the reagent in peptide synthesis, see Butyl chloroformate. The principle involved is illustrated by a procedure for the preparation of diethyl benzoylmalonate (3). Benzoic acid is condensed with cathyl chloride in toluene in the presence of triethylamine to produce the mixed anhydride (I), and an ethereal solution of ethoxymagnesium malonic ester (2), prepared from mulunic ester, magnesium, ethanol, and a trace of carbon tetrachloride as catalyst, is added... 

The reagent is prepared in about 50% yield by reaction of malonic acid and acetone with either acetic anhydride - or isopropenyl acetate, in each case in the presence of a catalytic amount of sulfuric acid. This acetonide is a strong acid and can be hydrolyzed under very mild conditions . since the methylene group is... 

Reaction with reactive-methylene compounds. Claisen" developed a method for the preparation of diethyl ethoxymethylenemalonate by heating a mixture of triethyl orthoformate, malonic ester, and acetic anhydride with a catalytic amount of zinc chloride. The yield cited is that obtained in a standardized procedure."... 

Duckworth used the reagent to prepare anhydrides of malonic acids, which are of interest because on pyrolysis they afford ketenes. 

Michael condensation. Cason prepared yS-methylglutaric anhydride starting with the condensation of methyl crotonate with diethyl malonate, carried out by... 

Mixed anhydride synthesis. A method widfely used for the synthesis of peptides provides a general method of acylation, illustrated by the benzoylation of diethyl malonate. Benzoic acid is converted into the triethylamine salt in toluene, and the solution is treated at 0 with ethyl chloroformate to form the mixed benzoic-carbonic anhydride, with precipitation of triethylamine hydrochloride. The second component, ethoxymagnesium malonic ester, is prepared from diethyl malonate in ethanol-ether... 

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