Organic Syntheses Collective Volume 2

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Organic Syntheses Collective Volume

Transcript of Organic Syntheses Collective Volume 2

Organic Syntheses, Coll. Vol. 2, p.1 (1943); Vol. 19, p.1 (1939).

-ACETAMINOCINNAMIC ACID[Cinnamic acid, -acetamido-]

Submitted by R. M. Herbst and D. Shemin. Checked by Reynold C. Fuson and E. A. Cleveland.

1. ProcedureA mixture of 58.5 g. (0.5 mole) of acetylglycine (p. 11) (Note 1), 30 g. (0.37 mole) of anhydrous sodium acetate, 79 g. (0.74 mole) of freshly distilled benzaldehyde, and 134 g. (1.25 moles) of 95 per cent acetic anhydride in a loosely corked 1-l. Erlenmeyer flask is warmed on the steam bath with occasional stirring until solution is complete (ten to twenty minutes). The resulting solution is boiled for one hour under reflux, cooled, and placed in a refrigerator overnight. The solid mass of yellow crystals is treated with 125 cc. of cold water and broken up with a stirring rod. The crystals are then transferred to a Bchner funnel and washed thoroughly with cold water (Note 2). After being dried in a vacuum desiccator over phosphorus pentoxide and potassium hydroxide, the crude azlactone weighs 6972 g. (7477 per cent of the theoretical amount). The product melts at 148150, and is sufficiently pure for preparative purposes (Note 3). In a 1-l. round-bottomed, short-necked flask 47 g. (0.25 mole) of the crude azlactone of acetaminocinnamic acid is dissolved by boiling with a mixture of 450 cc. of acetone and 175 cc. of water. Hydrolysis is completed by boiling under reflux for four hours. Most of the acetone is then removed by distillation at ordinary pressure on a steam bath. The residual solution is diluted with 400 cc. of water, heated to boiling for five minutes to ensure complete solution of the acetamino acid, and filtered (Note 4) and (Note 5). A small amount of undissolved material (0.20.5 g.) which remains on the filter is washed with 5075 cc. of boiling water. Any crystals which separate from the filtrate are redissolved by heating, after which the solution is boiled for five minutes with 10 g. of Norite and filtered with the aid of gentle suction while still almost at the boiling point (Note 5). The Norite is washed thoroughly on the funnel with two to four 50-cc. portions of boiling water to remove the crystals which separate during the filtration, and the washings are added to the main filtrate. After standing in a refrigerator overnight the colorless, crystalline needles are collected on a Bchner funnel (Note 6), washed with 150200 cc. of ice-cold water, and dried for several hours at 90100. The yield is 4146 g. (8090 per cent of the theoretical amount) of practically pure material, m.p. 191192 (Note 7).

2. Notes

1. The azlactone of -acetaminocinnamic acid may also be prepared by substituting the equivalent amount of glycine for acetylglycine and increasing the amount of acetic anhydride to three molecular proportions, but the yield is only about 4550 per cent of the theoretical amount. 2. If the excess benzaldehyde is not almost completely removed by repeated washing with water, a final wash with 5075 cc. of ether may be advantageous, although this causes some loss of azlactone owing to its solubility in ether. 3. The azlactone can be recrystallized from alcohol, from carbon tetrachloride, or from ethyl acetate with addition of petroleum ether. Aqueous solvents should be avoided, since the azlactone ring is easily opened by water. When alcohol is used for recrystallization, there is some danger of opening the azlactone ring with the formation of an ester, particularly on prolonged heating of the solution. 4. The solution may be filtered by gravity through a large folded filter (preferably in a steam-jacketed funnel), or through a Bchner funnel with gentle suction. 5. The solubility of -acetaminocinnamic acid in water decreases very rapidly on cooling below the boiling point of the solution. Since the solution is very nearly saturated with the product, a large share of the acid will crystallize in the funnel during filtration if the solution is allowed to cool too much. This property of the product makes it inadvisable to work with larger quantities. 6. Occasionally after treatment with Norite the solution is green owing to traces of iron and phenylpyruvic acid. If the crystals are still yellow at this point, the treatment with Norite should be repeated before the product is collected on a filter. 7. If further purification is desired, the product may be recrystallized from 600 cc. of boiling water, with a loss of about 5 per cent. The loss is due in part to hydrolysis of the product with the formation of phenylpyruvic acid.

3. DiscussionThe azlactone of -acetaminocinnamic acid has been prepared by heating a mixture of glycine, benzaldehyde, acetic anhydride, and anhydrous sodium acetate;1, 2 and from Nchloroacetylphenylalanine by treatment with acetic anhydride.2 -Acetaminocinnamic acid has been prepared from the corresponding azlactone by hydrolysis with either aqueous sodium hydroxide1 or with boiling water alone.2 This preparation is referenced from: Org. Syn. Coll. Vol. 2, 489 Org. Syn. Coll. Vol. 2, 519

References and Notes1. Erlenmeyer, Jr., and Frstck, Ann. 284, 48 (1895). 2. Bergmann and Stern, ibid. 448, 26 (1926).

Appendix Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number)petroleum ether Azlactone of -Acetaminocinnamic acid alcohol (64-17-5)

ethyl acetate (141-78-6) ether (60-29-7) acetic anhydride (108-24-7) sodium acetate (127-09-3) sodium hydroxide (1310-73-2) iron (7439-89-6) carbon tetrachloride (56-23-5) benzaldehyde (100-52-7) acetone (67-64-1) Norite (7782-42-5) potassium hydroxide (1310-58-3) Glycine (513-29-1) -Acetaminocinnamic acid, Cinnamic acid, -acetamido- (5469-45-4) Acetylglycine (543-24-8) Phenylpyruvic acid (156-06-9) phosphorus pentoxide (1314-56-3) N-chloroacetylphenylalanine (721-65-3)Copyright 1921-2005, Organic Syntheses, Inc. All Rights Reserved

Organic Syntheses, Coll. Vol. 2, p.3 (1943); Vol. 14, p.1 (1934).

ACETO-p-CYMENE[Acetophenone, 5-isopropyl-2-methyl-]

Submitted by C. F. H. Allen Checked by Reynold C. Fuson and Charles F. Woodward.

1. ProcedureA 1-l. three-necked flask is fitted with a dropping funnel, a stirrer, a thermometer for reading low temperatures (Note 1), and a condenser, to the upper end of which is attached a tube for disposing of the hydrogen chloride evolved (Note 2). A mixture of 200 cc. of carbon disulfide and 180 g. (1.35 moles) of anhydrous aluminum chloride is placed in the flask which is then immersed in an ice-salt freezing mixture and stirred very vigorously until the temperature of the mixture is 5 or below. A mixture of 175 g. (1.3 moles) of p-cymene and 110 g. (100 cc., 1.4 moles) of acetyl chloride is added from the dropping funnel at such a rate that the temperature never rises above 5. This addition requires about three and one-third hours (Note 3). The mixture is allowed to stand overnight and is then poured upon 1 kg. of cracked ice to which 200 cc. of concentrated hydrochloric acid has been added. The mixture is extracted with three 700-cc. portions of ether; the ether solution is dried over anhydrous calcium chloride and distilled at ordinary pressure from a Claisen flask provided with an indented column, until the temperature reaches 190. The material that remains in the flask is fractionally distilled twice under diminished pressure. The principal fraction is aceto-p-cymene, a pale yellow oil boiling at 124125/12 mm. (155157/30 mm.). It weighs 115125 g. (5055 per cent of the theoretical amount) (Note 4). About 50 g. of cymene is recovered (Note 5), and there is a small amount (1012 g.) of residual oil left in the flask (Note 6).

2. Notes1. Since it is impossible to read that part of the thermometer scale which extends into the reaction flask, a thermometer should be used which when in position has the zero point above the stopper of the flask. A thermometer reading from 50 to +50 is recommended. 2. A gas trap of the type shown in Fig. 1 is suitable for this purpose. Another gas trap is shown in Org. Syn. Coll. Vol. I, 1941, 97. Fig. 1

3. After about two-thirds of the mixture has been added the rate of addition may be increased somewhat. The time required for the addition depends on the efficiency of the cooling and stirring; the stirring must be vigorous. With one-half of these amounts in a 500-cc. flask, the time required is only about one and one-third hours since, under these conditions, it is easier to control the temperature. 4. From the first fractionation a fraction boiling over a 20 range is taken as crude ketone; e.g., at 2830 mm. the fraction is taken which boils at 145165. Much trouble is caused by the tendency of the ketone to become superheated. 5. Acetyl chloride gives a better yield and less high-boiling residue than acetic anhydride. 6. This procedure has also been used successfully in the acetylation of cumene and tert.-butylbenzene. At the low temperatures employed there is very little decomposition, as is shown by the small amount of high-boiling residue.

3. DiscussionAceto-p-cymene can be prepared by the action of acetyl chloride on p-cymene in the presence of anhydrous aluminum chloride1 or ferric chloride.2 This preparation is referenced from: Org. Syn. Coll. Vol. 2, 24 Org. Syn. Coll. Vol. 2, 543 Org. Syn. Coll. Vol. 3, 23 Org. Syn. Coll. Vol. 3, 446

Org. Syn. Coll. Vol. 4, 42 Org. Syn. Coll. Vol. 4, 62 Org. Syn. Coll. Vol. 4, 157 Org. Syn. Coll. Vol. 4, 162 Org. Syn. Coll. Vol. 4, 364 Org. Syn. Coll. Vol. 4, 387 Org. Syn. Coll. Vol. 4, 404 Org. Syn. Coll. Vol. 4, 554 Org. Syn. Coll. Vol. 4, 590 Org. Syn. Coll. Vol. 4, 715 Org. Syn. Coll. Vol. 4, 746 Org. Syn. Coll. Vol. 4, 755 Org. Syn. Coll. Vol. 4, 804 Org. Syn. Coll. Vol. 4, 807 Org. Syn. Coll. Vol. 4, 844 Org. Syn. Coll. Vol. 4, 960 Org. Syn. Coll. Vol. 4, 984 Org. Syn. Coll. Vol. 5, 196 Org. Syn. Coll. Vol. 5, 572 Org. Syn. Coll. Vol. 5, 580 Org. Syn. Coll. Vol. 5,