Ethanol from diethyl malonate

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. 

Barbituric acid, usually represented as the trione (1014 R1 = R2 = H), was first made about 1864 and it has no hypnotic properties. It may be made conveniently from diethyl malonate and urea in ethanolic sodium ethoxide <43OSC(2)60) and it does have a variety of biological properties without much practical use (71MI21301). The origin of the name is lost, although there are several plausible explanations associated with St. Barbara s feast day, a favourite Miinchen Kellnerin rejoicing in that given name, and even the Latin barba which is a beard or the business end of a key. 

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... 

The synthesis of barbituric acid can be best accomplished from diethyl malonate and urea, with an alkaline catalyst, such as sodium ethoxide in ethanol [113]. Barbituric acid-2- C has been prepared from urea- C and diethyl malonate [114]. The 4- C and 5- C compounds have been obtained by the pyrolysis of diethyl oxalacetate-3- C, which produced an equimolar mixture of 4- and 5- C barbituric acid after a rather lengthy procedure [115]. 

Synthesis. Dn-Isoleucine is synthesized in about 27% over-all yield by the method of Marvel (554). Diethyl sec.-butylmalonate (A) is prepared in 83% yield from diethyl malonate, sodium, absolute ethanol and sec.-butyl bromide (b.p. 91.3°C.) essentially by the method of Romburgb (673). a-Bromo- S-methylvaleric acid (B) is pr ared in about 67% yield by the alkaline hydrolysis of (A), isolation of sec.-butylmalonic acid ((j), and bromination and decarboxylation of (C). DL-Isoleucine (D), prepared by amination of (B), is recrystallized from 30% ethanol. It has been suggested (39, 485) that the product should be repeated recrystallized from 80% ethanol to free it from allo-isoleucine. It has been found in the writers laboratory that recrystallization from 20% ethanol is an effective purification procedure. The described s thesis is essentially that originated by Brasch and Friedman (125) and Ehrlich (237) and employed by Abd halden and Zeisset (39). 

Egri et al. investigated the one-pot synthesis of N-(3-chlorophenyl)-aminomethylenemalonate (250), starting from equimolar amounts of 3-chloroaniline, diethyl malonate, and ethyl formimidate hydrochloride or ethyl orthoformate (73ACH217). The reaction involving ethyl formimidate hydrochloride was conducted in the presence of triethylamine at 120-130°C for 2 hr and then at 140°C for 80 hr. The ethanol formed in the reaction was continuously distilled off. N-(3-Chlorophenyl)aminomethyl-enemalonate (250) was obtained in 98-99% yields. 

Another Methodfor 5 5-Diethyl Barbituric Acid. (This is a scaled down version.) 16 g of clean sodium is dissolved in 300 g of absolute ethanol. To this cooled solution is added 20 g of dry urea and 50 g of diethyl malonic ester (diethyl diethyl malonate). The mixture is heated in an autoclave (pressure cooker, very strong) for 4 to 5 hours at 100-110°. After removing from the autoclave, the mixture is cooled. Upon cooling, the sodium salt of diethyl barbituric acid separates, is filtered off, dissolved in water, and the free acid precipitated by the addition of hydrochloric acid. The acid is filtered and recrystallized from water, using decolorizing carbon, if necessary. Yield Depends on your ability to exclude H2O from the beginning of reaction. 

Masamune and co-workers reported that t-pr-box 22 can also be obtained from (5)-valinol by a similar strategy (see above). Thus, 21 was reacted with diethyl-malonate and the resulting diamide was treated with thionyl chloride followed by sodium hydroxide in a mixture of ethanol and tetrahydrofuran (THF) to yield t-pr-box 22 (Fig. 9.5). The synthesis of i-pr-box 22 can also be achieved directly by treatment of 21 with diethyl iminomalonate in the presence of triethylamine. ... 

Nine hundred and twenty-five milliliters of absolute ethanol (Note 1) is placed in a 2-1. three-necked round-bottomed flask, fitted with a mercury or glycerin-sealed stirrer (Note 2), dropping funnel, and reflux condenser. To this is added 46 g. (2 gram atoms) 2 of freshly cut sodium, a few pieces at a time and at such a rate that the reaction proceeds rapidly but the solvent does not reflux too vigorously. When most of the sodium has dissolved, a calcium chloride drying tube is fitted to the top of the condenser and 320 g. (2 moles) of redistilled diethyl malonate is added from the dropping funnel. Then 205 g. (2 moles) of 3-chlorocyclopentene (p. 42) (Note 3) is added at such a rate that a gentle reflux is maintained. Towards the end of the addition, it is desirable to test the reaction mixture with pH test paper, and the addition should be stopped if the solution becomes acidic. 

IV-Alkyl-substituted phthalimides 9 were easily transformed into mono-, di- or trisubslituted pyrazoles 10 via a one-pot addition/decyclization/cyclocondensation sequence <02JCS(P1)207>. 5-Silylpyrazoles can be prepared from condensation of silylalkynones with hydrazines <02T4975>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted pyrazolin-5-ones <02T3639>. 

Diethyl malonate adds to diethyl fumarate in a conjugate addition reaction promoted by sodium ethoxide in dry ethanol to give a tetraester, Diethyl fumarate is an excellent Michael acceptor because two ester groups withdraw electrons from the alkene, The mechanism involves deprotonation of the malonate, conjugate addition, and reprotonation of the product enolate by ethanol solvent, In this reaction two ester groups stabilize the enolate and two more promote conjugate addition. 

Either the tertiary amine or the quaternary ammonium salt can be stored as a stable equivalent of the exo-methylene compound. In our first example, the Mannich base with dimethylamine is first methylated with methyl iodide and then added to the conjugate addition reaction. Elimination of trimethylamine, which escapes from the refluxing ethanol as a gas, reveals the exo-methylene ketone in which the methylene group is exo to a chain. Fast conjugate addition of the stabilized enolate of diethyl malonate produces the product. 

Solid-phase synthesis of substituted pyrazolones 550 from polymer-bound /3-keto esters 549 has been described (Scheme 68) <2001EJ01631>. Trisubstituted pyrazole carboxylic acids were prepared by reaction of polymer-bound arylidene- or alkylidene-/3-oxo esters with phenylhydrazines <1999S1961>. 2-(Pyrazol-l-yl)pyrimi-dine derivatives were prepared by cyclocondensation of ethyl acetoacetate and (6-methyl-4-oxo-3,4-dihydropyrimi-din-2-yl)hydrazine with aromatic aldehydes <2004RJC423>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted-pyrazolin-5-ones <2002T3639>. Reactions of hydrazines with A -acetoacetyl derivatives of (45 )-4-benzyloxazolidin-2-one (Evans oxazolidinone) and (2R)-bornane-10,2-sultam (Oppolzer sultam) in very acidic media gave pyrazoles retaining the 3(5)-chiral moiety <1999S157>. 

Malonodihydroxamic acid 800 cf-801 Diethyl malonate (80 g, 0.5 mole) is treated with an anhydrous ethanolic solution (11) containing hydroxylamine (1 mole) liberated from its hydrochloride by the calculated amount of sodium ethoxide in ethanol. To this i,s added a solution of sodium (25 g, 1.1 moles) in anhydrous ethanol (500 ml), whereupon the disodium salt of the product begins to separate, a process that is complete (78 g) after a few hours. 

Transfer 5 g salicylaldehyde (0.041 mol), 7.2 g diethyl malonate (0.045 mol), 25 ml absolute ethanol, 0.5 ml piperidine (freshly distilled), 0.02 ml (1 drop) glacial acetic acid and a few pieces of anti-bumping clips into a dry 50 ml round bottom flask. Provide the flask with a double wall reflux condenser (water-cooled) and instal either a CaClj-guard tube or a cotton plug at the open-end of the reflux condenser so as to prevent the reaction mixture from absorbing atmospheric moisture. 

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