Sodium diethylmalonate

In 1885, Just reported the reaction of sodium diethylmalonate with Af-phenylbenzimino chloride to provide 11. Thermal cyclization provided 12. This work was virtually untouched for several decades, but laid the groundwork for further development. 

Although most of these early reactions were conducted with allylic acetates, reactions of allylic carbonates, trifluoroacetates, and phosphates also occur. Sodium diethylmalonate also reacts with allylic alcohols in the presence of the iridium-triphenylphosphite catalyst. However, the alcohol itself does not act as a leaving group. Instead, transesterification occurs with one equivalent of malonate nucleophile to form a more labile ester leaving group. 

The palladium-catalyzed Heck-type reaction of methylenecyclopropane 66 in the presence of soft nucleophiles such as sodium diethylmalonate gives a mixture of isomeric alkenes 70 and 71 (Scheme 8.32) [77]. In this process, there is first a carbopalladation of the double bond of 66 giving the cyclopropylcarbinylpalladium in-... 

Two-carbon chain extension at the carboxyl end, mimicking biosynthesis, uses the malonic ester route (102). After reduction of the carboxyl to an alcohol, the readily displaced mesylate is prepared and reacted with sodium diethylmalonate. Saponification and decarboxylation gives the chain extended product in high yield. 

In an alternative route to the prostaglandins from cyclopentadiene, Holton has made use of the technique of so-called carbo-palladation , whereby the two side-chain fragments are attached in sequence to the double bonds of cyclopentadiene via appropriate palladium complexes. Thus treatment of the enamine (58), derived from cyclopentadiene, with lithium tetrachloropalladate and sodium diethylmalonate led to the palladium complex (59) which with di-iso-... 

Displacement of the halogen atom in 1-bromomethylcarborane occurs with difficulty or not at all on treatment with nucleophilic reagents such as iodide ion, sodium diethylmalonate, triethylamine, or hexamethylenetetra-... 

The greater reactivity of the fluoro complex, already evaluated using kinetic measurements (Brown and Raju, 1966), thus leads to yields much superior to those obtained by the action of sodium diethylmalonate on chlorobenchrotrene (XXV). Furthermore, the reaction below, opposite to that which occurs with the chloro complex (XXV), may be carried out in a yield of 94% (after oxidation). 

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. 

Diethylbarbituric acid. In a dry 250 ml. distilling flask, fitted with a thermometer reaching to within 3-4 cm. of the bottom and a condenser, place 51 g. of clean sodium and add 110 g. (140 ml.) of super-dr ethyl alcohol (Section 11,47,5). When all the sodium has reacted, introduce 20 g. of ethyl diethylmalonate and 7 0 g. of dry imea (dried at 60 for 4 hours). Heat the flask in an oil bath and slowly distil off the ethyl alcohol. As soon as the temperature of the liquid reaches 110-115°, adjust the flame beneath the bath so that the contents of the flask are maintained at this temperature for at least 4 hours. Allow the flask to cool somewhat, add 100 ml. of water and warm until the solid (veronal-sodium) dissolves. Pour the solution into a beaker, and add a further 100 ml. of water but containing 7 0 ml. of concentrated siilplmric acid this will hberate the veronal from the sodium derivative. The veronal usually crystallises out if it does not, add a few more drops of dilute sulphuric acid until the solution is acid to Congo red. Heat the contents of the beaker, with stirring and the addition of more water if necessary, until all the veronal dissolves at the boiling point. Allow the hot solution to cool, filter off the crystals of veronal and diy in the air. The yield is 12 g., m.p. 190°. 

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 condensation of 1 mol of ethyl malonate with two mols of ethyl iodide in the presence of two mols of sodium ethoxide gives a good yield of ethyl diethylmalonate. Upon aUowing the latter to react with the theoretic quantity of urea in the presence of an alcoholic solution of sodium ethoxide, veronal (diethylbarbituric acid or diethylmalonylurea) is produced. 

Substitution of the nine position is a common transformation for acridines. An optimized method for preparing the 9-carboxamides uses BOP/DMF <99SC4341>. Reaction of 9-isothioacridines with the sodium anion of diethylmalonate is followed by alkylation with bromoacetate to afford the spiro[dihydroacridine-9(10i/)-thiazolidines] <99H(51)137>. 

Omeprazole is obtained [15] by the reaction of acetyl ethyl propionate 1 with ammonia to give ethyl -3-amino-2,3-dimethyl acrylate 2. Compound 2 was converted to to 2,4-dihydroxy-3,5,6-trimethyl pyridine 3 by treatment with methyl diethylmalonate. Treatment of compound 3 with phosphorous oxychloride produced 2,4-dichloro-3,5/6-trimethyl pyridine 4. 4-Chloro-3/5,6-trimethyl pyridine 5 was obtained by treatment of compound 4 with hydrogen. On treatment of compound 5 with hydrogen peroxide and acetic acid, 4-chloro-3,5,6-trimethyl-pyridine-N-oxide 6 was produced. Treatment of compound 6 with acetic anhydride gave 4-chloro-2-hydroxymethyl-3,5-dimethyl pyridine 7 which was converted to 2-hydroxymethyl-3,5-dimethyl-4-methoxypyridine 8 by treatment with sodium methoxide. Compound 8 was treated with thionyl chloride to produce 2-chloromethyl-3,5-dimethyl-4-methoxypyridinc 9. Compound 9 interacts with 5-methoxy-2-mercaptobenzimidazole to give 5-methoxy 2-[((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)thio]-lH-bcnzimidazole 10 which is oxidized to omeprazole 11. 

Bromo-2-isopropylanisole (191) was prepared from p-bromoanisole (190). It was caused to react with magnesium and ethylene oxide to obtain the alcohol (192). Its bromoderivative on heating with diethylmalonate and sodium ethoxide followed by hydrolysis with alcoholic potassium hydroxide yielded the substituted malonic acid. This on heating furnished acid (193). Its acid chloride in benzene underwenr cyclization with aluminium chloride to yield tetralone (194). It was... 

The reaction of the tetrafluoroethylene trimer with one equivalent of diethylmalonate and two equivalents of sodium hydride in dry ether gives a mixture of 5-carboethoxy-6-ethoxy-2,3,4-tris(trifluoromethyl)-2-pyran and 5-carboethoxy-6-ethoxy-2,3,4-tris(trifluoromethyl)-4-pyran in a 2.1 1 ratio with a total yield of 71% (98JFC(88)169). 

The synthesis of 10-oxa-l 1-deoxyprostanoids that is of prostanoids with a 7-lactone structure has been reported in the patent literature82 and from a research group from the Research Triangle Institute83. The latter synthesis started with diethyl-2-(3-cyclooctenyl)-malonate 112 which can be prepared according to the literature M, 85) jjy a treating the sodium salt of diethylmalonate with 3-bromocyclooctene or 1,2-dibromocyclooctane. 

The first group93) chose an approach by which the introduction of the upper side chain was achieved by reaction of the optically active epoxide 165 with the sodium derivative of diethylmalonate to the mixture of the isomers 166 and 167. The desired isomer 166 was isolated in 20% yield by chromatography on silica gel. The stereocontrolled opening of the epoxide which had been prepared out of 163 via the mesylate 164 was the prerequisite for the correct configuration of the prostanoid side chains in compound 171. 

Sodium hydride (0.8 g) was added to 50 ml THE and diethylmalonate added over 5 minutes. l-Bromo-2,4-dimethoxybenzene (1.08 g) was then added in one portion and the reaction flask cooled to — 20°C. A few crystals of 1,10-phenanthroline were added as an indicator and the flask further cooled to —60°C. A few drops of n-BuLi were added until the brown color of the indicator persisted. Thereafter n-BuLi (3.05 mmol) and 0.91ml diisopropylamine was added to form lithium diisopropyl-amide. In order to observe a product conversion of 97%, a total of 2.5 ml EDA added drop wise via cannula in 24 minutes at —20°C to —24°C. The solution was acidified using 1.0 M HCl and the organic portion isolated, washed with brine and isolated in 93.2% purity as a yellow oil. H-NMR data supplied. 

Continued investigation of MeC(CH2Asl2)3 has led to isolation of two nor-hetero-adamantanes, 28 and 29 (R = COOEt), from reactions with, respectively, diethylmalonate and sodium hydroselenide. As—As distances are 2.469 and 2.483 A respectively, while in the related cyclic triarsine 30 the separation is reduced to 2.42 A . 

Sodium hydride (60% oil dispersion, 0.15 g, 0.38 mmol) was washed with hexane (2x2 mL) and THF (1x2 mL). Note exercise great care with NaH, particularly after the hexane wash the NaH should be kept under nitrogen or argon.) To a suspension of oil-free sodium hydride in THF (5mL) was added diethylmalonate (0.770 mL, 0.38 mmol). After 15 min of stirring, the resulting diethyl malonate anion solution was added via a cannula to a solution of the allylic benzoate (131 mg, 0.56 mmol), Pd(PPh3)4 (45 mg, 0.039 mmol), and triphenylphosphine (100 mg. 

In a 2 liter, 3 necked flask with a stirrer, dropping funnel, thermometer, reflux head, nitrogen stream and mercury manometer (if available) stir 230 ml dry methanol and 32.4g sodium meth-oxide under nitrogen until dissolved. Add llOg diethylmalonate and stir 10 minutes. Add portionwise 75g 90% pure 3-nonene-... 

---