Sodium—continued ethoxide

Ethyl phenylethylmalonate. In a dry 500 ml. round-bottomed flask, fitted with a reflux condenser and guard tube, prepare a solution of sodium ethoxide from 7 0 g. of clean sodium and 150 ml. of super dry ethyl alcohol in the usual manner add 1 5 ml. of pure ethyl acetate (dried over anhydrous calcium sulphate) to the solution at 60° and maintain this temperature for 30 minutes. Meanwhile equip a 1 litre threenecked flask with a dropping funnel, a mercury-sealed mechanical stirrer and a double surface reflux condenser the apparatus must be perfectly dry and guard tubes should be inserted in the funnel and condenser respectively. Place a mixture of 74 g. of ethyl phenylmalonate and 60 g. of ethyl iodide in the flask. Heat the apparatus in a bath at 80° and add the sodium ethoxide solution, with stirring, at such a rate that a drop of the reaction mixture when mixed with a drop of phenolphthalein indieator is never more than faintly pink. The addition occupies 2-2 -5 hoius continue the stirring for a fiuther 1 hour at 80°. Allow the flask to cool, equip it for distillation under reduced pressure (water pump) and distil off the alcohol. Add 100 ml. of water to the residue in the flask and extract the ester with three 100 ml. portions of benzene. Dry the combined extracts with anhydrous magnesium sulphate, distil off the benzene at atmospheric pressure and the residue under diminished pressure. C ollect the ethyl phenylethylmalonate at 159-160°/8 mm. The yield is 72 g. 

This ester (70 g) and diethyl carbonate (250 mg) were stirred at 90°C to 100°C while a solution of sodium ethoxide [from sodium (7.8 g) and ethanol (1 54 ml)] was added over 1 hr. During addition, ethanol was allowed to distill and after addition distillation was continued until the column heat temperature reached 124°C. After cooling the solution to 90°C, dimethyl sulfate (33 ml) was followed by a further 85 ml of diethyl carbonate. This solution was stirred and refluxed for 1 hr and then, when Ice cool, was diluted with water and acetic acid (10 ml). The malonate was isolated in ether and fractionally distilled to yield a fraction boiling at 148°C to 153°C/0.075 mm, identified as the alpha-methyl malonate. This was hydrolyzed by refluxing for 1 hr at 2.5N sodium hydroxide (350 ml) and alcohol (175 ml), excess alcohol was distilled and the residual suspension of sodium salt was acidified with hydrochloric acid to give a precipitate of the alpha-methyl malonic acid. This was decarboxylated by heating at 180°C to 200°Cfor 30 minutes and recrystallized from petroleum ether (BP 80°C to 100°C) to give 2-(2-fluoro-4-biphenylyl)propionic acid, MP 110°C to 111°C. 

A. Triethyl oxalylsuccinate. In a 2-1. three-necked flask equipped with a sealed stirrer and a reflux condenser bearing a calcium chloride drying tube is placed 356 ml. (276 g., 6.00 moles) of anhydrous ethanol (Note 1). Sodium (23 g., 1.0 g. atom) is added in small portions at a rate sufficient to keep the ethanol boiling. External heating is required to dissolve the last portions of the metal. After all the sodium has dissolved, the excess ethanol is removed by distillation at atmospheric pressure as the mixture becomes pasty, dry toluene is added in sufficient amounts to permit stirring and to prevent splattering of the salt. Distillation and addition of toluene is continued until all the ethanol is removed and the contents of the flask reach a temperature of 105° (Note 2). The sodium ethoxide slurry is cooled to room temperature and 650 ml. of anhydrous ether is added, followed by 146 g. (1.00 mole of diethyl oxalate. To the yellow solution there is added 174 g. (1.00 mole) of diethyl succinate, and the mixture is allowed to stand at room temperature for at least 12 hours. 

Degradation of octaacetyllactobiononitrile. (Sodium ethoxide.y To 750 ml. of chloroform containing the impure octaacetyllactobiononitrile prepared from 200 g. of lactose, a solution of 15 g. of sodium in 750 ml. of methanol was added the solution was maintained at a low temperature and was shaken continuously. A jelly-like mass precipitated. When the precipitation was ended, 750 ml. of water and 50 ml. of acetic acid were added. The chloroform layer was separated and the water phase was evaporated in vacuo to a thick sirup. This was dissolved in 400 ml. of 96% ethanol, 65 g. of a,ai-benzylphenylhydrazine was added and the solution was heated in a water bath for thirty minutes. Assisted by seeding, crystallization of the hydrazone of the 3-( 9-D-galactopyranosyl)-D-arabinose was completed in five hours. The crystals were filtered and washed well with 80% ethanol yield 60-67 g., m. p. 223-225°. 

As rapidly as possible, after removal of the ethanol, the flask is fitted with a rubber-sealed stirrer, a dropping funnel, a distilling head containing a thermometer, and a condenser arranged for distillation into a flask protected by a calcium chloride tube. There are then added 300 ml. of dry diethyl carbonate, 80 ml. of dry toluene, and 58.5 g. (0.50 mole) of phenylacetonitrile (Note 2). The flask is heated, with good stirring, and the cake of sodium ethoxide soon dissolves. When distillation has started, dry toluene is added dropwise at about the same rate that the distillate is collected. Approximately 200-250 ml. of toluene should be added in a period of 2 hours (Note 3) while stirring and distillation are continued. 

Two grams of sodium were dissolved in absolute alcohol, freshly distilled over quicklime, in a flask fitted with a reflux condenser. As sodium ethoxide began to separate out, more alcohol was added until just sufficient was present to retain the product in soln. at the room temp.—40 c.o. were needed. The flask was fitted with a 2-hole stopper fitted with delivery and egress tube to which calcium chloride tubes were attached. Hydrogen sulphide washed in water, and dried by a long column of calcium chloride was passed rapidly into the soln. A fine crystalline precipitate formed in the soln., and increased in amount with the continued passage of the gas. When the soln. was sat. with gas, the precipitate was collected, rapidly filtered, washed with absolute alcohol, and dried in vacuo over calcium chloride. The precipitate weighed 0 25 grm. When benzene or ether is added to the soln., a precipitate of pure anhydrous sodium hydrosulphide is obtained. This is washed and dried as before. 

Less basic malonic ester anions may be employed for the twofold alkylation of dibromides. Cyclic 1,1-dicarboxylic esters are formed, if the reaction is executed in an appropriate manner. In the synthesis of cyclobutane diester A the undesired open-chain tetraester B was always a side product (J.A. Cason, 1949), the malonic ester and its monoalkylation product were always only partially ionized. Alkylation was therefore slow and intermolecular reactions of mono-alkyl intermediates with excess malonic ester prevailed. If the malonic ester was dissolved in ethanol containing sodium ethoxide, and 1,3-dibromopropane as well as more sodium ethoxide were added slowly to the solution, 63% of A and only 7% of B were isolated. The latter operations kept the malonic ester and its monoalkylated product in the ionic form, and the dibromide concentration low, so that the intramolecular reaction was favored against intermolecular reactions. The continuous addition of base during the reaction kept the ethoxide concentration low, which helped to prevent decomposition of the bromide by this nucleophile. 

In an initial step, the sodium derivative of ethyl (3-benzoylphenyl) cyanoacetate is prepared as follows (3-benzoylphenyl)acetonitrile (170 9) is dissolved in ethyl carbonate (900 g). There is added, over a period of 2 hours, a sodium ethoxide solution [prepared from sodium (17.7 g) and anhydrous ethanol (400 cc)], the reaction mixture being heated at about 105° to 115°C and ethanol being continuously distilled. A product precipitates. Toluene (500 cc) is added, and then, after distillation of 50 cc of toluene, the product is allowed to cool. Diethyl ether (600 cc) is added and the mixture is stirred for 1 hour. The crystals which form are filtered off and washed with diethyl ether (600 cc) to give the sodium derivative of ethyl (3-benzoylphenyl)cyanoacetate (131 g). 

An ethanolic solution of sodium ethoxide is prepared by reacting 3 g of sodium with 300 ml of absolute ethanol. 30 g of estradiol are dissolved in the resultant solution and there are then added thereto, with stirring, 30 ml of n-propyl bromide. Reaction is continued for 3 hours with stirring at 60°C and then the reaction mixture is concentrated under vacuum at 30°C to about 50 ml. The residue is taken up in 500 ml of benzene and then washed twice with 250 ml of a 0.25 N solution of sodium hydroxide and then with distilled water to neutrality. The solution is then dried over sodium sulphate and concentrated to give 32 g of crude product (yield 93%), which on recrystallization from 100 ml of methanol gives 31 g (yield 89%) of pure product MP 100°-101°C. 

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