Diethyl malonate preparation

Bromo-5,5-dimethylhexane (87 grams) was added to a solution of the sodium salt of diethyl malonate prepared from diethyl malonate (72 grams), sodium (10.4 grams), and ethyl alcohol (230 ml). 

To a suspension of the Na salt of diethyl malonate, prepared in anhyd EtjO (50 mL) from Na (0.575 g, 25 mmol) and redistilled diethyl malonate (4.0 g, 25 mmol), was added at once powdered 4-chloroquinazo-line (12, R = H X = Cl 4.9 g, 29.8 mmol). The mixture was stirred and refluxed for 20 h. The solids were filtered off and added to HjO (50 mL). After neutralization with 1.5 M H SO, 2.2 g of crude diethyl 2-(quinazolin-4-yl)malonate was collected. The ethereal filtrate from the solid was shaken with 3 M NaOH soin. Three layers separated, a dark-amber oil, a yellow aqueous layer, and a yellow ethereal layer. The oil and aqueous layers were combined and neutralized with 1.5 M H SO, yielding an additional 1.1 g of the crude product yield 3.3 g (46%) mp 85.5-86.5 °C (hexane). 

Barbituric acid and 2-thiobarbituric acid are readily prepared by the condensation of diethylmalonate with urea and thiourea respectively, in the presence of sodium ethoxide. The use of substituted derivatives of urea and thiourea and of diethyl malonate will clearly lead to a wide range of barbituric and thiobarbituric acids having substituents in the i, 3, or 5 positions. 

Malonic acid may be prepared from chloroacetic acid by the following series of reactions (compare Diethyl Malonate, Section 111,153) —... 

Diethyl malonate has uses other than m the synthesis of carboxylic acids One particu larly valuable application lies m the preparation of barbituric acid by nucleophilic acyl substitution with urea... 

These compounds are prepared m a manner analogous to that of barbituric acid itself Diethyl malonate is alkylated twice then treated with urea... 

Show by writing a suitable sequence of reactions how you could prepare pentobarbital from diethyl malonate (The structure of pentobar... 

Section 21 9 Michael addition of the enolate ions derived from ethyl acetoacetate and diethyl malonate provides an alternative method for preparing their a alkyl derivatives... 

Show how you could prepare each of the following compounds Use the starting material indicated along with ethyl acetoacetate or diethyl malonate and any necessary inorganic reagents Assume also that the customary organic solvents are freely available... 

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

Malonic ester synthesis (Section 21 7) Synthetic method for the preparation of carboxylic acids involving alkylation of the enolate of diethyl malonate... 

Ring-Closure Reactions. Some interesting dyes are prepared by ring-closure reactions at or near the dye-forming step of a synthetic sequence. The stmctural identity of thiacyanine was originally estabUshed by the reaction of diethyl malonate and o-aminothiophenol. 

Diphenylcinnoline can be prepared from benzil monophenylhydrazone in the presence of about 80% sulfuric acid (49MI21200). Synthetically more important, however, is the cyclization of mesoxalyl chloride phenylhydrazones under Frledel-Crafts -conditions (61JCS2828). As outlined in Scheme 67, the starting mesoxalate phenylhydrazones are obtained by coupling dlazotized aromatic amines with diethyl malonate. After conversion... 

Replacement of the methyl ketone moiety in 78 by a phenyl sulfoxide, interestingly, leads to a relatively potent uricosuric agent with diminished antiinflammatory action. This effect in lowering serum levels or uric acid leads to the use of this drug in the treatment of gout. Alkylation of diethyl malonate with the chlorosulfide, 79, gives the intermediate, 80. The pyrazolodione (81) is prepared in the usual way by condensation with hydrazobenzene. Careful oxidation of the sulfide with one equiv-... 

Preparation of Diethyl (1-Methyl-2-Pentynyl) Malonate To a solution of 2B.6 g of sodium in 430 ml of absolute ethanol were added 200 g of diethyl malonate. About half of the alcohol was removed by distillation in vacuo, and thereafter a solution of 200 g of 2-bromo-3-hexyne in 100 ml of anhydrous ether was added slowly to the reaction mixture. 

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 synthesis of the right-wing sector, compound 4, commences with the prochiral diol 26 (see Scheme 4). The latter substance is known and can be conveniently prepared in two steps from diethyl malonate via C-allylation, followed by reduction of the two ethoxy-carbonyl functions. Exposure of 26 to benzaldehyde and a catalytic amount of camphorsulfonic acid (CSA) under dehydrating conditions accomplishes the simultaneous protection of both hydroxyl groups in the form of a benzylidene acetal (see intermediate 32, Scheme 4). Interestingly, when benzylidene acetal 32 is treated with lithium aluminum hydride and aluminum trichloride (1 4) in ether at 25 °C, a Lewis acid induced reduction takes place to give... 

This compound was prepared by heating benzene-1,2-diamine (2.16 g, 20 mmol) and the appropriate derivative of diethyl malonate (10 mmol) in 1,2,4-trichlorobenzene (15 rnL) at 190—195 "C for 2 h. The resulting solution was cooled and the precipitated product was collected and washed with benzene, followed by petroleum ether.253... 

Diethyl malonate or a derivative (0.25 mol) and benzene-1,2-diamine (27 g, 0.25 mol) were added to a solution of NaOEt prepared from sodium (11.5 g. 0.5 g-atom) and EtOH (300 mL). The EtOH was distilled off, finally under reduced pressure, and the residue was heated at 180-200 C under N2 for 4 h and then stirred with ice. The mixture was acidified with coned HC1 and the resulting solid was collected, washed with H20 and recrystallized (EtOH) with the addition of decolorizing charcoal if necessary. 

A solution of the tetrachloride (1.99 g, 5 mmol) in benzene (50 mL) was added to a solution of ethyl sodiomalonate, which was prepared from metallic Na (0.46 g, 0.02 mol) and diethyl malonate (20 mmol, 3.2 g), in anhyd EtOH (30 mL), and the resulting mixture was refluxed for 2 h. The mixture was poured into H2Q, and then extracted with benzene (2x50mL). The benzene extract was dried (MgSOd) and concentrated in vacuo, and the residue was recrystallized (EtOH) yield 1.3 g (81%) mp 158-159 C. Overall yield 67%. 

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