Ethyl malonate preparation

One-pot malonic ester synthesis. A separate hydrolysis step can be avoided by use of the dilithium salt of ethyl malonate, prepared by reaction of the ester with 2 eq. of hthium isopropylcyclohexylamide (4, 306-309) in THF at -78°. HMPT and the alkyl halide are then added and the reaction mixture is allowed to come to room temperature for 2 hr. Decarboxylation is then effected by overnight reflux. 

To 2 ml. of a freshly prepared dilute aqueous solution of sodium nitroprusside, add 2 drops of ethyl malonate and shake then add 2-3 drops of 10% aqueous sodium hydroxide solution and shake again. A red coloration at once appears, but fades in a few minutes to pale brown,... 

It follows therefore that ethyl malonate can be used (just as ethyl aceto- acetate) to prepare any mono or di-substituted acetic acid the limitations are identical, namely the substituents must necessarily be alkyl groups (or aryl-alkyl groups such as CjHjCHj), and tri-substituted acetic acids cannot be prepared. Ethyl malonate undergoes no reaction equivalent to the ketonic hydrolysis of ethyl acetoacetate, and the concentration of the alkali used for the hydrolysis is therefore not important. 

While the sodium ethoxide solution is cooling, prepare a solution of 7 7 g. of finely powdered iodine in 60 ml. of ether. When this solution is ready, add 9 ml. (9 6 g.) of ethyl malonate to the ethanolic sodium ethoxide solution, mix w ell and then allow to stand for 30-60 seconds not longer) then cautiously add the ethereal solution of the iodine, mixing thoroughly during the addition in order to avoid local overheating by the heat of the reaction. (If, after the ethyl malonate has been added to the sodium ethoxide, a considerable delay occurs before the iodine is added, the yield of the final product is markedly decreased.)... 

Since Grignard reagents can easily be obtained from aryl halides, they are of special value in the s nthesis of many aromatic compounds, particularly as, for reasons already stated (pp. 270, 276), aromatic compounds cannot generally be prepared by means of ethyl acetoacetate and ethyl malonate. 

Ethyl malonate can be conveniently prepared by neutralising a solution of monochloroacetic acid with sodium bicarbonate, then heating with potassium cyanide to form sodium cyanoacetate ... 

Where R and R are identical, the dialkylmalonic ester may be prepared in one operation by treating 1 mol of ethyl malonate with 2 mots each of sodium ethoxide and the alkyl halide (usually bromide or iodide). 

Pelargonic acid (n-Nonoic acid), CH3(CH2),COOH. Equip a 1-litre, three-necked flask with a reflux condenser, a mercury-sealed stirrer, a dropping funnel and a thermometer. Place 23 g. of sodium, cut in small pieces, in the flask, and add 500 ml. of anhydrous n-butyl alcohol (1) in two or three portions follow the experimental details given in Section 111,152 for the preparation of a solution of sodium ethoxide. When the sodium has reacted completely, allow the solution to cool to 70-80° and add 160 g. (152 ml.) of redistilled ethyl malonate rapidly and with stirring. Heat the solution to 80-90°, and place 182 5 g. (160 ml.) of n-heptyl bromide (compare experimental details in Section 111,37) in the dropping funnel. Add the bromide slowly at first until precipitation of sodium bromide commences, and subsequently at such a rate that the n-butyl alcohol refluxes gently. Reflux the mixture until it is neutral to moist litmus (about 1 hour). 

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... 

These compounds yield, on hydrolysis, the free acids, which, like all acids containing two carbo.xyl groups attached to the same carbon atom, lose COj on heating. Thus, ethyl malonic acid yields butyric acid. In this way the synthesis of monobasic acids may be readily effected. Malonic ester, moreover, may be used in the preparation of cyclic compounds as well as of tetrabasic and also dibasic acids of the malonic acid series ( Perkin). To give one illustration malonic ester, and ethylene bromide in presence of sodium alcoholate, yield triniethyleiic dicarbo.xylic ester and tetramethylene tetracarbo.xylic ester. The first reaction takes place in two steps,... 

A large number of trialkylacetic acid esters have been prepared by mixed Kolbe electrolysis of ethyl malonates [164]. Crossed-coupling is also used for chain extension. Extension by two carbon atoms is achieved with benzyl succinates [153, 180-182], whereby the purification of the chain extended fatty acid is simphfied by using the benzyl half ester [181a]. 

High antiscorbutic power is also reported to be shown by a derivative of L-ascorbic acid in which the enolic hydroxyl group at C2 is replaced by an amino group. 3,4-Isopropylidene-L-threonic acid (LX), prepared from 5,6-isopropylidene-L-ascorbic acid, is converted into the 2-acetyl-3,4-isopropylidene-L-threonyl chloride (LXI) and this is then allowed to react with the sodium derivative of ethyl malonate. 

Cyclobutanedicarboxylic acid has been prepared by hydrolysis of the ethyl ester,1 or of the half nitrile, 1-cyano-l-car-boxycyclobutane.2 The ethyl ester has been prepared by condensation of ethyl malonate with trimethylene bromide1 or chloro-bromide.3 The half nitrile has been prepared by condensation of trimethylene bromide with ethyl cyanoacetate followed by hydrolysis of the ester to the acid.2... 

The heating of diethyl 2-(2,4,6-trichlorophenyl)hydrazino methylene-malonate, prepared from 2,4,6-trichlorophenylhydrazine and EMME in ethanol at -10°C, gave ethyl l-(2,4,6-trichIorophenyl)-5-hydroxypyra-zole-4-carboxylate at 170-175°C for 45 min in 82% yield (89USP4804398). 

Ethyl 3-oxoalkanoates when not commercially available can be prepared by the acylation of tert-butyl ethyl malonate with an appropriate acid chloride by way of the magnesium enolate derivative. Hydrolysis and decarboxylation in acid solution yields the desired 3-oxo esters [59]. 3-Keto esters can also be prepared in excellent yields either from 2-alkanone by condensation with ethyl chloroformate by means of lithium diisopropylamide (LDA) [60] or from ethyl hydrogen malonate and alkanoyl chloride usingbutyllithium [61]. Alternatively P-keto esters have also been prepared by the alcoholysis of 5-acylated Mel-drum s acid (2,2-dimethyl-l,3-dioxane-4,6-dione). The latter are prepared in almost quantitative yield by the condensation of Meldrum s acid either with an appropriate fatty acid in the presence of DCCI and DMAP [62] or with an acid chloride in the presence of pyridine [62] (Scheme 7). 

Different syntheses of y-amino-/3-ketoeter derivatives from iV-protected L-aminoacids by Al,Al -carbonyldiimidazole activation and treatment with the magnesium enolate of hydrogen ethyl malonate are described. These compounds are useful intermediates in the preparation of active amino acid analogues, as illustrated and summarized in equation 103. 

P-Keto estersS F.thyl dilithiomalonate, prepared from ethyl malonate with n-butyllithium in THF containing a trace of 2,2 -bipyridyl (as indicator), reacts with acid chlorides at about —65° to give, after acidic work-up, / -keto esters. For highest yields at least 1.7 equivalent of the acid chloride is required. Reported isolated yields (nine examples) are 90-99%. 

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). 

Now that fumaric and maleic acid are available commercially, the most convenient method of preparing the above ester consists in condensing ethyl malonate with ethyl fumarate1 or ethyl maleate.2 It has also been prepared by condensing malonic ester with ethyl chlorosuccinate 3 and with ethyl ethoxysucci-nate.4... 

Methyl ethyl acetic acid may be prepared from methyl ethyl malonic ester by hydrolysis and subsequent heating of the methyl ethyl malonic acid.1 The yield by this method, in the preparation of large quantities, is about 61 per cent of the theoretical amount based on the malonic ester used. The acid was first prepared by Saur2 from methyl ethyl acetoacetic ester. It has also been made by oxidation of the corresponding aldehyde with chromic acid.3... 

In most cases convergent types of syntheses are the most cost effective and preferred for various reasons. However, that was not the case with ERH-1 as it will show in the following examples. In the convergent approach (see Scheme 3) it was assumed that barbituric acid would be a cheap source ( 4 per kg) for the pyrimidine portion since it was prepared from inexpensive materials such as ethyl malonate and urea with sodium ethoxide as a condensing agent. Numerous reports [4] have shown that barbituric acid is easily converted to 2,4,6-trichloropyrimidine by heating with phosphorus oxychloride and a trialkylamine. Our intent was to couple 2,4,6-trichloropyrimidine 10 to 2,2-dimethyl-1-indanone followed by various reactions that would lead to ERH-1 [5] as shown in Scheme 3. 

The synthetic route to acridine-containing polymers is outlined in Scheme I. 9-Methyl acridine (II) was prepared via 9-ethyl-malonate acridine by the method of Campbell et al (14), from 9-chloroacridine (I, Kodak), (mp. 117-8°C from ligroin). 9-(3hydro-xyethyl) acridine (III) was synthesized via the condensation of formaldehyde with II (15) (mp. 154-6°C, from ethanol-water). Metha-cryloylchloride, freshly distilled, was reacted with III in dry THF with pyridine as base to give IV, 2-(9-acridyl) ethylmethacrylate, purified by chromatography with silica gel/toluene to give red gum (IR 5.85 ym ester carbonyl stretch). 

Partial saponification of malonic ester occurs with cold alcoholic potassium hydroxide to give potassium ethyl malonate in 82% yield. Esters of dibasic acids having the carboxyl groups farther apart are cleaved in a similar manner under these conditions, e.g., the preparation of the halfester of a-methylpimelic acid (59%)- ... 

An ethanolic solution of sodium ethoxide is prepared by the addition of 11.5 g. (0.5 gram atom) of sodium to 160 ml. of absolute ethanol (p. 142) under a reflux condenser. After cooling to room temperature, 160 g. (1.0 mole) of ethyl malonate is added to the solution, and this is followed by the dropwise addition of 63.2 g. (0.60 mole) of benzyl chloride. The resulting mixture is refluxed for 1 hour, and then most of the ethanol is distilled off. The residue is treated with water, and the organic layer is separated and distilled. There is collected 80 g. of unreacted malonic ester, b.p. 91-96°/12 mm, pressure and 107 g. (85 yield based on malonic ester consiuned) of benzylmalonic ester, b.p. 163-170°/12 mm. 

One of the most valuable methods of preparing carboxylic acids makes use of ethyl malonate (malonic ester), CH2(COOC2H5)>, and is called the malonic ester synthesis. This synthesis depends upon (a) the high acidity of the a-hydrogens of malonic ester, and (b) the extreme ease with which malonic acid and substituted malonic acids undergo decarboxylation. (As we shall sec, this combination of properties is more than a happy accident, and can be traced to a single underlying cause.)... 

---