Diethyl malonate, hydrolysis

Diethyl malonate is prepared commercially by hydrolysis and estenfication of ethyl cyano acetate... 

Fig. 2. Synthesis of uma2enil (18). The isonitrosoacetanihde is synthesized from 4-f1iioroani1ine. Cyclization using sulfuric acid is followed by oxidization using peracetic acid to the isatoic anhydride. Reaction of sarcosine in DMF and acetic acid leads to the benzodiazepine-2,5-dione. Deprotonation, phosphorylation, and subsequent reaction with diethyl malonate leads to the diester. After selective hydrolysis and decarboxylation the resulting monoester is nitrosated and catalyticaHy hydrogenated to the aminoester. Introduction of the final carbon atom is accompHshed by reaction of triethyl orthoformate to...

Beryllium, calcium, boron, and aluminum act in a similar manner. Malonic acid is made from monochloroacetic acid by reaction with potassium cyanide followed by hydrolysis. The acid and the intermediate cyanoacetic acid are used for the synthesis of polymethine dyes, synthetic caffeine, and for the manufacture of diethyl malonate, which is used in the synthesis of barbiturates. Most metals dissolve in aqueous potassium cyanide solutions in the presence of oxygen to form complex cyanides (see Coordination compounds). 

Reaction of o-toluidine with chloral hydrate in presence of hydroxylamine hydrochloride and subsequent treatment with H2SO4 gave the isatin derivative 337. Bromination of 337 followed by reaction with sodium diethyl malonate gave 338. Catalytic reduction with Pd/C gave the oxoindole derivative 339 that upon hydrolysis with aqueous NaOH followed by... 

Incorporation of a carbonyl group into the alkyl side chain also proved compatible with biologic activity. The key intermediate (76) is obtainable by Michael addition of the anion from diethyl malonate to methylvinyl ketone followed by ketalization with ethylene glycol. Condensation of 76 with hydrazobenzene leads to the pyrazolodione hydrolysis of the ketal group affords ketasone (78). ... 

The malonic ester synthesis can also be used to prepare cydoalkane-carboxvlic acids. For example, when 1,4-dibromobutanc is treated with diethyl malonate in the presence of 2 equivalents of sodium ethoxide base, the second alkylation step occurs intrcunotecidariy to yield a cyclic product. Hydrolysis and decarboxylation then give cvclopentanecarboxylic acid. Three-, four-, five-. 

The preparation described here of 3-cyclopentene-1-carboxylic acid from dimethyl malonate and cis-1,4-dichloro-2-butene is an optimized version of a method reported earlier3 for obtaining this often used and versatile building block.6 The procedure is simple and efficient and requires only standard laboratory equipment. 3-Cyclopentene-1-carboxylic acid has previously been prepared through reaction of diethyl malonate with cis-1,4-dichloro(or dibromo)-2-butene in the presence of ethanolic sodium ethoxide, followed by hydrolysis of the isolated diethyl 3-cyclopentene-1,1-dicarboxylate intermediate, fractional recrystallization of the resultant diacid to remove the unwanted vinylcyclopropyl isomer, and finally decarboxylation.2>7 Alternatively, this compound can be obtained from the vinylcyclopropyl isomer (prepared from diethyl malonate and trans-1,4-dichloro-2-butene)8 or from cyclopentadiene9 or cyclopentene.10 In comparison with the present procedure, however, all these methods suffer from poor selectivity, low yields, length, or need of special equipment or reagents, if not a combination of these drawbacks. 

Michael additions to acceptor-substituted dienes are often followed by (spontaneous or induced) cyclizations. This was already noted by Vorlander and Groebel4 who obtained a substituted 1,3-cyclohexanedione by treatment of 6-phenyl-3,5-hexadien-2-one with diethyl malonate (equation 5). Obviously, the 1,4-addition product which is formed initially then undergoes cyclization, ester hydrolysis and decarboxylation. Similarly, reaction of methyl sorbate with methyl 4-nitrobutyrate gave the 1,6-adduct which was reductively cyclized to 6-methyl-l-azabicyclo[5.3.0]decane18 (equation 6). 

Condensation of 3-chloromethylbenzo[6]thiophene with diethyl malonate followed by hydrolysis, decarboxylation, Arndt-Eistert homo-logization, hydrolysis, and cyclization of the derived acid chloride with anhydrous stannic chloride yielded 2-methyl-4-keto-l,2,3,4-tetrahy-drodibenzothiophene (47). ... 

Diethyl malonate can be converted into its enolate anion, which may then be used to participate in an Sn2 reaction with an alkyl halide (see Section 10.7). Ester hydrolysis and mild heating leads to production... 

The mechanistic steps can be deduced by inspection of structures and conditions. Enolate anion formation from diethyl malonate under basic conditions is indicated, and that this must attack the epoxide in an Sn2 reaction is implicated by the addition of the malonate moiety and disappearance of the epoxide. The subsequent ring formation follows logically from the addition anion, and is analogous to base hydrolysis of an ester. Ester hydrolysis followed by decarboxylation of the P-keto acid is then implicated by the acidic conditions and structural relationships. 

The Michael addition of nucleophiles to coumarins catalyzed by solid bases provides an interesting approach to the synthesis of 4-substituted 3,4-dihydrocumarins, because with the conventional Michael catalysts the alkaline hydrolysis of the 8-lactone predominates (Scheme 44). Results were obtained when the Michael addition of diethyl malonate to coumarin was catalyzed by the activated Ba(OH)2 292). An unusual 1,2-addition-elimination process at the C = 0 bond was observed. The mechanism of this reaction was explained on the basis of the microcrystalline structure of the catalyst. It was suggested that the rigid coumarin molecule interacts with the Ba ions through the lone-pair electrons of both oxygen atoms of the... 

Ethyl hydrogen malonate may be prepared from diethyl malonate by controlled hydrolysis with potassium hydroxide (see also Expt 5.147, Note (1)). 

Reaction with ethylpropiolate The carbene reacts with ethyl propiolate to form isomeric vinyl ether derivatives (2) of diethyl malonate. The products are converted into the corresponding ketones on hydrolysis. 

By analogy, the chemical Claisen condensation using the enolate anion from diethyl malonate in Figure 2.10 proceeds much more favourably than that using the enolate from ethyl acetate. The same acetoacetic acid product can be formed in the malonate condensation by hydrolysis of the acylated malonate intermediate and decarboxylation of the gem-diacid. 

The heart of the preparation of capsaicin is a malonic ester synthesis. The first step is bromination of the primary alcohol by phosphorous tribromide. The resulting primary alkyl bromide is used to alkylate the sodium salt of diethyl malonate. A substituted malonic acid derivative is obtained following basic hydrolysis of the ester groups. 

Cyclopropane carboxylic acid (1) Cyclopropane bromide + KCN - cyclopropane cyanide followed by hydrolysis (2) Ethylene dibromide + diethyl malonate - cyclopropane dicarboxylic acid followed by saponification and monodecarboxylation via heating... 

Hydrolysis of the alkylated diethyl malonate (a diethyl alkylmalonic ester) gives a malonic acid derivative. 

Alkylation or acylation of malonic ester (diethyl malonate), followed by hydrolysis and decarboxylation, to give substituted acetic acids, (p. 1079)... 

One of the best methods of amino acid synthesis is a combination of the Gabriel synthesis of amines (Section 19-20) with the malonic ester synthesis of carboxylic acids (Section 22-16). The conventional malonic ester synthesis involves alkylation of diethyl malonate, followed by hydrolysis and decarboxylation to give an alkylated acetic acid. 

With these two esters, the choice of base is important nucleophilic addition can occur at the ester carbonyl, which could lead to transesterification (with alkoxides), hydrolysis (with hydroxide), or amide formation (with amide anions). The best choice is usually an alkoxide Identical with the alkoxide component of the ester (that is, ethoxide for diethyl malonate methoxide for dimethyl malonate). Alkoxides (pKd 16) are basic enough to deprotonate between two carbonyl groups but, should substitution occur at C=0, there is no overall reaction. 

Previously cyclopropane-1,1-dicarboxylic acid had been prepared2-4 by hydrolysis of the corresponding diester. The preparation of 1,1-dicarboalkoxycyclopropanes by a conventional double alkylation of diethyl malonate with 1,2-dibromoethane was severely complicated by the recovery of unreacted diethylmalonate. This required a rather difficult distillation to separate starting material and product. In fact, many commercially offered lots of cyclopropane diester contain extensive amounts of diethyl malonate. Furthermore, preparation of the diacid required a separate and relatively slow saponification of the diester.5... 

The 1-phenyl 3-carboxaldehyde (148, R = H, R = Ph) underwent reaction at 20° with diethyl malonate in ether, to which one drop of piperidine was added, to give the methylenemalonate (151) (90%). Alkaline hydrolysis gave the diacid (153) (70%), which was de-carboxylated in refluxing hydrochloric acid to the jS-acrylic acid (154) (83 %). A Wittig reaction of the aldehyde (148, R = H, R = Ph) with triethyl phosphonoacetate and sodium ethoxide in DMF at 10° gave the ethyl acrylate (152, 46%), which was hydrolyzed also to the acid (154) (78%).i 9... 

The synthesis of one of the agents begins with nucleophilic aromatic displacement of bromine by cyanide in the highly fluorinated compound 78. Acid hydrolysis of the nitrile (79), followed by esterification of the newly formed acid, affords ester 80. Base-catalyzed condensation of the intermediate with diethyl malonate leads to the tricarbonyl derivative 81. 

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