Modified Claisen condensation

The ratio of the reagents is 2 oxime 4 base 1 ester and is consistent with similar procedures used for a modified Claisen condensation. The yield is based on the ester. When a ratio of reagents of 1 oxime 2 base 1 ester was used, a yield of 21 % based on the ester was obtained. 

Modified Claisen condensation. Silyl ketene acetals and methyl esters (important ) react in the presence of Me3Al in toluene to afford mixed methyl/silyl acetals of (3-ketoesters. 

This is a modified Claisen condensation between two molecules of acetyl-CoA resulting in the appearance of acetoacetyl-CoA and separation of CoA. The reaction is reversible and the enzyme catalysing the condensation also catalyses the reverse thiolysis. If a specific deacylase is present, the acetoacetate is liberated and the equilibrium is distributed until the acetyl-CoA is completely transformed into acetoacetate. 

The solution of sodium methyl sulfide in absolute alcohol is transferred to a 3-I. three-necked flask, which is placed on a steam bath and fitted with a dropping funnel, a reflux condenser, and a mechanical stirrer. The solution is heated until the alcohol begins to boil. Heating is then discontinued and 302 g. (3.7s moles) of ethylene chlorohydrin (Note 5) is added dropwise with efficient stirring over a period of about two hours (Note 6). The reaction mixture is concentrated by distilling as much of the alcohol as possible on the steam bath. The mixture is then allowed to cool and the sodium chloride removed by filtration. The flask is rinsed, and the sodium chloride washed with three loo-cc. portions of 95 per cent alcohol. The combined filtrate and washings are concentrated on the steam bath under reduced pressure until no further distillate passes over. The residue is then transferred to a modified Claisen flask (Org. Syn. Coll. Vol. i, 125) and fractionally distilled under reduced pressure. The yield is 238-265 g. (74-82 per cent of the theoretical amount based on the sodium used) of a product boiling at 68-7o°/20 mm. 

In a 1-L rbf attached to a Dean-Stark trap, equipped with a reflux condenser is placed distilled aniline (1, 46.5 g, 45.5 mL, 0.5 mol), commercially available ethyl acetoacetate (5, 65 g, 63.5 mL, 0.5 mol), benzene (100 mL) and glacial AcOH (1 mL). The flask is heated at about 125 °C, and the water which distills out of the mixture with the refluxing benzene is removed at intervals. Refluxing is continued until no more water separates (9 mL collects in about 3 hrs) and then for an additional 30 min. The benzene is then distilled under reduced pressure, and the residue is transferred to a 125 mL modified Claisen flask with an insulated column. The flask is heated in an oil or metal bath maintained at a temperature not higher than 120 °C while the forerun of 1 and 5 is removed and at 140-160 °C the product distills giving 78-82 g, 76-80% yield of 6. 

Prepare 26 g. of molecular sodium in a 1500 ml. round-bottomed flask (Section II,50,d, Method 1). Cover the sodium with 625 ml. of sodium-dried A.R. benzene fit the flask with an efficient reflux condenser protected from the air by means of a calcium chloride (or cotton wool) guard tube. Add 151 5 g. of diethyl adipate (Sections 111,99 and 111,100) in one lot, followed by 1 6 ml. of absolute ethyl alcohol. Warm the flask on a water bath until, after a few minutes, a vigorous reaction sets in and a cake of the sodio compound commences to separate. Keep the flask well shaken by hand during the whole of the initial reaction. After the spontaneous reaction has subsided, reflux the mixture on a water bath overnight, and then cool in ice. Decompose the product with ice and dilute hydrochloric acid (1 1) add the acid until Congo red paper is turned blue. Separate the benzene layer, and extract the aqueous layer with 100 ml. of benzene. Wash the combined extracts with 100 ml. of 5 per cent, sodium carbonate solution and 160 ml. of water dry over a KWe anhydrous magnesium sulphate. Remove the benzene under atmospheric pressure (Fig. II, 13, 4, but with modified Claisen flask), and fractionate the residue under reduced pressure. Collect the 2-carbethoxy-epelopentanone at 108-111°/15 mm. (96 g.). Upon redistillation, the product boils at 102°/H mm. 

For the liberation of N-methylethylamine, a 1-1. Claisen flask is equipped with a 250-ml. separatory funnel and an efficient condenser for distillation. The receiver is cooled with a mixture of acetone and dry ice (Note 7). A solution of 100 g. (2.5 moles) of sodium hydroxide in 100 ml. of water is added to the flask and kept at about 100° by heating on a steam bath. The aqueous solution of N-methylethylamine hydriodide is added to this solution through the separatory funnel in the course of 1.5 hours. After the addition is complete, the final solution is heated for an additional 30 minutes. Crude N-methylethylamine, b.p. 30-70°, collects in the cooled receiver. It is purified by distillation from 25 g. of solid potassium hydroxide in a 250-ml. modified Claisen flask fitted with a 25-cm. Fenske column and a receiver cooled by dry ice and acetone. N-Methylethylamine is collected at 34-35° weight 49-55 g. (83-93%) 2 3 4 5d 1.3830. 

In a 3-I. round-bottomed flask fitted with a 3-ft. indented column to which is attached a condenser set for downward distillation are placed 321 g. (3 moles) of methylaniline, 300 g. of formic acid (85-90 per cent), and 1800 cc. of toluene (Note 1). The solution is distilled slowly. As long as the azeotrope containing water is present, the temperature of the vapor is 87-88° when the water has been removed, the temperature rises to 108-110° (Note 2). The distillation is continued until approximately 1500 cc. of toluene has been collected (five to six hours). The residue is then transferred to a modified Claisen flask (Org. Syn. Coll. Vol. 1, 125) and distilled in vacuo, the portion boiling at 114-121° at 8 mm. being collected. This has a freezing point of 13.6-13.7° d i-5S3 I SSS- The yield is 380-393 g. (93-97 per cent of the theoretical amount). This product is satisfactory for the preparation of aldehydes (p. 11). Upon redistillation it boils at 117-121° at 8 mm., 130-132° at 22 mm. The freezing point and refractive index are unchanged. 

In a 1-1. three-necked round-bottomed flask, wrapped with aluminum foil to exclude light, and equipped with a mechanical stirrer, a reflux condenser, and an addition funnel, is suspended 37 g. (0.17 mole) of red mercuric oxide (Note 1) in 330 ml. of carbon tetrachloride (Note 2). To the flask is added 30.0 g. (0.22 mole) of 3-chlorocyclobutaneearboxylic acid (Note 3), and the mixture is heated to reflux while stirring. To the mixture is added dropwise a solution of 40 g. (0.25 mole) of bromine in 180 ml. of carbon tetrachloride as fast as possible (4-7 minutes) without loss of bromine from the condenser (Note 4). After a short induction period, carbon dioxide is evolved at a rate of 150-200 bubbles per minute (Note 5). The solution is allowed to reflux until the rate of carbon dioxide evolution slows to about 5 bubbles per minute. This will usually take 25-30 minutes (Note 6). The mixture is then cooled in an ice bath, and the precipitate is removed by filtration. The residue on the funnel is washed with carbon tetrachloride, and the filtrates are combined. The solvent is removed by distillation using a modified Claisen distillation apparatus with a 6-cm. Vigreux column, and vacuum distillation of the residual oil gives 13-17 g. (35-46%) of... 

Tetrahydrofuran (36 g., 0.5 mole) (Note 1) is added to a mixture of potassium iodide (332 g., 2 moles), 85% orthophosphoric acid (231 g., 135 ml., 2 moles), and phosphoric anhydride (65 g.) (Notes 2, 3, and 4) in a 1-1. three-necked flask equipped with a sealed mechanical stirrer, a reflux condenser, and a thermometer. The mixture is stirred and heated at its reflux temperature for 3 hours, during which time a dense oil separates from the acid layer. The stirred mixture is cooled to room temperature, and 150 ml. of water and 250 ml. of diethyl ether are added (Note 5). The ether layer is separated, decolorized with dilute aqueous sodium thiosulfate solution, washed with cold saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The ether is removed by distillation on a steam bath, and the residue is distilled under reduced pressure from a modified Claisen flask. The portion boiling at 108-110°/10 mm. is collected. The yield of colorless 1,4-diiodobutane ( o 1-615 df 2.300) (Note 6) is 143-149 g. (92-96%). 

A) a-Bromoisocaproic Acid.—Five hundred grams (4.3 moles) of commercial isocaproic acid is mixed with 250 cc. of benzene in a 2-1. round-bottomed flask, and the water and benzene are removed by distillation through a short column until the temperature of the vapors reaches ioo°. The temperature rises rapidly as soon as the last of the benzene is removed. The residual acid is cooled to room temperature, 743 g. (4.65 moles, 243 cc.) of dry bromine (Note 1) is added, and the flask is fitted with a long condenser and placed in an oil bath. The top of the condenser is connected to an empty 500-cc. Erlenmeyer flask which acts as a safety flask, and this in turn leads to a gas-absorption trap (Note 2). Ten cubic centimeters of phosphorus trichloride is added to the mixture through the top of the condenser, and the flask is heated to 80-85°. The bromination proceeds smoothly at this temperature and is allowed to continue for eight to fifteen hours until the dark red color of bromine disappears from the condenser. When it has, the temperature is raised to 100-105° and kept there two hours. The contents of the flask are transferred to a i-l. modified Claisen flask or a flask attached to a Widmer column and distilled. The fraction... 

In a dry 200-cc. flask fitted with a ground-in reflux condenser and protected from moisture with a calcium chloride tube are placed 66 g. (0.32 mole) of a-bromonaphthalene (Note 1), 35 g. (0.39 mole) of dry powdered cuprous cyanide (Note 2), and 30 cc. of pyridine (Note 3) in the order mentioned. This mixture is heated in a Wood s metal bath (Note 4) at 215-225° for fifteen hours. The resulting dark brown solution is poured while still hot (about ioo°) into a flask containing 150 cc. of aqueous ammonia (sp. gr. 0.90) and 150 cc. of water. About 140 cc. of benzene is added, and the flask is stoppered and shaken until all the lumps have disintegrated. After the mixture has cooled to room temperature, 100 cc. of ether is added and the mixture filtered (Note 5). The filtrate is transferred to a i-l. separatory funnel and the aqueous layer separated (Note 6). The ether-benzene layer is washed successively with (a) four 100-cc. portions of dilute aqueous ammonia (Note 7), (b) two 100-cc. portions of 6 N hydrochloric acid (Note 8), (c) two 100-cc. portions of water, and (d) two 100-cc. portions of saturated sodium chloride solution. The ether and benzene are removed by distillation from a water bath, and the residue is distilled under reduced pressure from a 125-cc. modified Claisen flask. The temperature rises rapidly, and the yield of colorless a-naphthonitrile, b.p. i73-i74°/27 mm. (i66-i69°/i8 mm.) is 40-44 g. (82-90 per cent of the theoretical amount) (Notes 9 tnd 10). 

B. 0-Carbomethoxypropionyl chloride. In a 1-1. flask (Note 6) bearing a reflux condenser are placed 264 g. (2 moles) of methyl hydrogen succinate and 290 ml. (4 moles) of thionyl chloride (Note 7), and the solution is warmed in a bath at 30-40° for 3 hours (Note 8). The condenser is replaced by a modified Claisen still head, the excess thionyl chloride is removed on a steam bath in vacuo, and the /3-carbomethoxypropionyl chloride is distilled (Notes 9 and 10). The yield of colorless product is 270-278 g. (90-93%), b.p. 92-93°/18 mm. (Notes 11 and 12). 

The heavier chlorocyclohexanone layer is separated and combined with three 150-ml. ether extracts of the aqueous phase, and washed with 150 ml. of water and then with 200 ml. of saturated sodium chloride solution. After filtration (gravity) through anhydrous sodium sulfate the ether is removed and the residue vacuum-distilled in a modified Claisen flask. The fraction (300-340 g.) boiling below 100° at 10 mm. (Note 5) is collected (Note 6). This material is then fractionated carefully under reduced pressure by means of a 42-in. modified Vigreux column (heated) with a total condensation variable takeoff head (Note 7). The yield of 2-chlorocyclohexanone boiling at 90-91°/14-15 mm. is 240-265 g. (61-66%) (Notes 8 and 9). 

To 340 g. (6 moles) of dry, powdered potassium hydroxide (Note 1) in a 500-cc. short-neck round-bottom flask (Note 2) is added 167 g. (1 mole) of /3-chloropropionaldehyde acetal (p. 26). The mixture is shaken vigorously and attached at once to a 3-bulb Glinsky, or other suitable column, connected to a water condenser set for distillation. The flask is heated in an oil bath at 210-2200 until nothing more distils (Note 3). The distillate is transferred to a separatory funnel and the lower aqueous layer is removed. The acrolein acetal is dried over 10 g. of potassium carbonate, filtered and distilled from a modified Claisen flask (Org. Syn. 1, 40). The yield is 98 g. (75 per cent of the theoretical, amount) of a product which boils at 122-126°. 

In a 500-cc. modified Claisen flask (Org. Syn. 1, 40) are placed 400 g. of cydohexanol (Note 1) and 12 cc. of concentrated sulfuric acid, and the flask is connected to a condenser and receiver. It is then placed in an oil bath which is heated to a temperature of 130-140°. The distillation is continued until only a small residue remains and the odor of sulfur dioxide is apparent. Toward the end of the distillation the temperature of the bath may be raised to 150°. The receiver is surrounded with an ice bath (Note 2) during the entire distillation which requires from five to six hours. 

In a s-1. round-bottom flask equipped with a mechanical stirrer are mixed 385 g. (335 cc.) (3.8 moles) of 95 per cent furfural (Org. Syn. 1, 49) (Note 1) and 3 1. of water. Then 500 g. (630 cc.) (8.6 moles) of acetone is added. The mixture is stirred and cooled to io° and to it is added 75 cc. of 33 per cent sodium hydroxide solution (Note 1), whereupon some heat is generated. Without cooling, the stirring is continued for four hours. At the end of this time 10 per cent sulfuric acid is added until the mixture is acid to litmus (about 350 cc.) (Note 2). The two layers which have formed are separated and the upper aqueous layer is distilled (Note 3) under ordinary pressure until the distillate no longer forms two layers. The bottom layer of this distillate is added to the original lower layer and distilled under reduced pressure from a i-l. modified Claisen flask (Org. Syn. 1, 40) provided with an air condenser and heated in an oil bath. The... 

When the addition of the bromine is complete, the flask is attached to a condenser set for distillation, and the carbon tetrachloride and excess cyclohcxene arc distilled from a water bath (Notes 4 and 5). The dark-colored residue is transferred to a 500-cc. modified Claisen flask (Org. Syn. 1, 40) and distilled under reduced pressure. There is a small low-boiling fraction, and then pure dibromocyclohexane distils at 108 ii2°/25 mm. The yield is 238 281 g. (73 86 per cent of the theoretic al amount) (Notes 6 and 7). 

The solution is then transferred to a continuous extractor and extracted with ether for about 16 hours. The ether extract is added in convenient portions to a 250-ml. modified Claisen flask fitted with a condenser and a suitable fraction-cutter for distilla-1 ion under reduced pressure. The ether is removed by distillation under the diminished pressure of a water pump, and the residue is then distilled at about 10 mm. pressure. After a small fore-run which weighs 2-5 g., the product distils as a clear, colorless, viscous oil at 62-66°/9-10 mm. n 1.4513. The yield is 00-95 g. (74-79%) (Notes 3 and 4). 

A convenient apparatus for the distillation is a modified Claisen flask whose side arm is provided with a short water-cooled condenser. A fraction-cutter of the pig type is satisfactory. 

The /3-chloropropionic acid is best isolated by direct distillation under reduced pressure (Note 1) using a 250-cc. modified Claisen flask (Org. Syn. 1, 40). The nitric acid is collected up to ioo°/20 mm. using a water condenser. The condenser is then removed and the residual 0-chloropropionic acid is fractionated, collecting as pure product the portion boiling at 105-107720 mm. The yield is 31-31.5 g. (54-55 per cent of the theoretical amount) (Note 2). The product solidifies on cooling and melts at 41-41.5°. 

The material is transferred (Note 4) to a modified Claisen flask having a fractionating side arm, and the chloroform is distilled off completely imder reduced pressure (without being condensed). The dimethylpjrrole is collected at 51-53°/8 mm. or 78-8o°/25 mm. only a small residue (4-5 g., b.p. 8o-85°/2S mm.) remains. The product weighs 68-72 g. (81-86 per cent of... 

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