Acid cyanides Claisen condensation

Reaction of sugar lactone with ester enolate (the Claisen condensation) gives -keto ester, the resulting 1,3-dicarbonyl compound immediately reacts with the hydroxyl group present in the same molecule to afford a lactol with an axial hydroxyl group. In a recent example shown in O Scheme 4 [8], the product of the reaction was further transformed to the corresponding nitrile or amide by addition of cyanide or a Ritter reaction with benzonitrile in the presence of TMSOTf as a Lewis acid. 

They are both chrysanthemic acid esters of (5-benzylfuran-3-yl)methanol (Elliott alcohol, 1) [15]. Patented methods [16] for the industrial preparation of Elliotf s alcohol are demanding or such as to be hardly exploited in industrial-scale plants. For instance, in one of these methods [17] (5-benzyl-3-furyl)methanol is obtained by a sequence of Claisen condensation of benzyl cyanide and a dialkyl succinate, hydrolysis, esterification, protection of the ketone group, formylation, cyclization to 5-benzyl-3-furfuryl ester and reduction to alcohol with lithium aluminium hydride. 

Vinylacetic acid. Place 134 g. (161 ml.) of allyl cyanide (3) and 200 ml. of concentrated hydrochloric acid in a 1-htre round-bottomed flask attached to a reflux condenser. Warm the mixture cautiously with a small flame and shake from time to time. After 7-10 minutes, a vigorous reaction sets in and the mixture refluxes remove the flame and cool the flask, if necessary, in cold water. Ammonium chloride crystallises out. When the reaction subsides, reflux the mixture for 15 minutes. Then add 200 ml. of water, cool and separate the upper layer of acid. Extract the aqueous layer with three 100 ml. portions of ether. Combine the acid and the ether extracts, and remove the ether under atmospheric pressure in a 250 ml. Claisen flask with fractionating side arm (compare Fig. II, 13, 4) continue the heating on a water bath until the temperature of the vapour reaches 70°. Allow the apparatus to cool and distil under diminished pressure (compare Fig. II, 20, 1) , collect the fraction (a) distilling up to 71°/14 mm. and (6) at 72-74°/14 mm. (chiefly at 72 5°/ 14 mm.). A dark residue (about 10 ml.) and some white sohd ( crotonio acid) remains in the flask. Fraction (6) weighs 100 g. and is analytically pure vinylacetic acid. Fraction (a) weighs about 50 g. and separates into two layers remove the water layer, dry with anhydrous sodium sulphate and distil from a 50 ml. Claisen flask with fractionating side arm a further 15 g. of reasonably pure acid, b.p. 69-70°/12 mm., is obtained. 

Place 75 g. (74 ml.) of benzyl cyanide (Section IV,160), 125 g. (153 ml.) of rectifled spirit and 150 g. (68 ml.) of concentrated sulphuric acid in a 750 ml. round-bottomed flask, fitted with an efficient reflux condenser. Reflux the mixture, which soon separates into Wo layers, gently for 8 hoius, cool and pour into 350 ml. of water. Separate the upper layer. Dissolve it in about 75 ml. of ether (1) in order to facilitate the separation of the layers in the subsequent washing process. Wash the ethereal solution carefully with concentrated sodium bicarbonate solution until effervescence ceases and then with water. Dry over 10 g. of anh3 drous magnesium sulphate for at least 30 minutes. Remove the solvent with the aid of the apparatus shown in Fig. II, 13, 4 and distil from an air bath (Fig. II, 5, 3). The ethyl phenylacetate passes over at 225-229° (mainly 228°) as a colourless liquid the yield is 90 g. Alternatively, the residue after removal of the ether may be distilled in a Claisen flask under diminished pressm (Fig. II, 20, 1) collect the ester at 116-lI8°/20 mm. 

Fit a 1500 ml. bolt-head flask with a reflux condenser and a thermometer. Place a solution of 125 g. of chloral hydrate in 225 ml. of warm water (50-60°) in the flask, add successively 77 g. of precipitated calcium carbonate, 1 ml. of amyl alcohol (to decrease the amount of frothing), and a solution of 5 g. of commercial sodium cyanide in 12 ml. of water. An exothermic reaction occurs. Heat the warm reaction mixture with a small flame so that it reaches 75° in about 10 minutes and then remove the flame. The temperature will continue to rise to 80-85° during 5-10 minutes and then falls at this point heat the mixture to boiling and reflux for 20 minutes. Cool the mixture in ice to 0-5°, acidify with 107-5 ml. of concentrated hydrochloric acid. Extract the acid with five 50 ml. portions of ether. Dry the combined ethereal extracts with 10 g. of anhydrous sodium or magnesium sulphate, remove the ether on a water bath, and distil the residue under reduced pressiu-e using a Claisen flask with fractionating side arm. Collect the dichloroacetic acid at 105-107°/26 mm. The yield is 85 g. 

In a 5-I. round-bottom flask, fitted with a mechanical stirrer and reflux condenser, are mixed 1150 cc. of water, 840 cc. of commercial sulfuric acid and 700 g. of benzyl cyanide (preparation III, p. 9). The mixture is heated under a reflux condenser and stirred for three hours, cooled slightly and then poured into 2 1. of cold water. The mixture should be stirred so that a solid cake is not formed the phenylacetic acid is then filtered off. This crude material should be melted under water and washed by decantation several times with hot water. These washings, on cooling, deposit a small amount of phenylacetic acid which is filtered off and added to the main portion of material. The last of the hot water is poured off from the material while it is still molten and it is then transferred to a 2-1. Claisen distilling flask and distilled in vacuo. A small amount of water comes over first and is rejected about 20 cc., containing an appreciable amount of benzyl cyanide, then distils. This fraction is used in the next run. The distillate boiling i76-i89°/5o mm. is collected separately and solidifies on standing. It is practically pure phenylacetic acid, m. p. 76-76.5° it amounts to 630 g. (77.5 per cent of the theoretical amount). As the fraction which is returned to the second run of material contains a considerable portion of phenylacetic acid, the yield actually amounts to at least 80 per cent. 

Nucleophilic addition to C=0 (contd.) ammonia derivs., 219 base catalysis, 204, 207, 212, 216, 226 benzoin condensation, 231 bisulphite anion, 207, 213 Cannizzaro reaction, 216 carbanions, 221-234 Claisen ester condensation, 229 Claisen-Schmidt reaction, 226 conjugate, 200, 213 cyanide ion, 212 Dieckmann reaction, 230 electronic effects in, 205, 208, 226 electrons, 217 Grignard reagents, 221, 235 halide ion, 214 hydration, 207 hydride ion, 214 hydrogen bonding in, 204, 209 in carboxylic derivs., 236-244 intermediates in, 50, 219 intramolecular, 217, 232 irreversible, 215, 222 Knoevenagel reaction, 228 Lewis acids in, 204, 222 Meerwein-Ponndorf reaction, 215 MejSiCN, 213 nitroalkanes, 226 Perkin reaction, 227 pH and, 204, 208, 219 protection, 211... 

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). 

A SOLUTION of 250 g. (1.51 moles) of chloral hydrate (Note i) in 450 cc. of warm water (50-60°) is placed in a 3-I. round-bottomed flask bearing a reflux condenser and thermometer (Note 2). The condenser is temporarily removed and 152.5 g. (1.52 moles) of precipitated calcium carbonate added this is followed by 2 cc. of amyl alcohol (Note 3) and a solution of 10 g. of sodium cyanide (Note 4) in 25 cc. of water. Althou the reaction is exothermic, the reaction mixture is heated with a low flame so that it reaches 75° in about ten minutes at this point heating is discontinued. The temperature continues to rise to 80-85° during five to ten minutes and then drops. As soon as the temperature begins to fall the solution is heated to boiling and refluxed for twenty minutes. The mixture is then cooled to 0-5° in an ice bath, acidified with 215 cc. of concentrated hydrochloric acid (sp. gr. 1.18) and extracted with five loo-cc. portions of ether (Note 5). The combined ether extracts are dried with 20 g. of anhydrous sodium sulfate, the ether is removed by distillation from a steam bath, and the residue distilled in vacuum from a Claisen flask with a fractionating side... 

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