(Hive Addict)
06-10-03 02:24
No 439015
      Synthesis of arylpropylamines from allyl chloride
(Rated as: excellent)

Cf. Post 438668 (not existing)

Synthesis of arylpropylamines. I. From allyl chloride

TM Patrick Jr, ET McBee, HB Hass
JACS 68 (1946) 1009

[...] It was possible to prepare a number of arylchloropropanes, many of them new, from allyl chloride by these techniques. These compounds are suitable as intermediates in the synthesis of arylpropylamines by ammonolysis with ammonia or amines. The aminations were carried out in an autoclave at 125-160C for reaction times of four to nine hours. In some cases aqueous solutions of ammonia or methylamine were used, but alcoholic solutions resulted in somewhat better yields and mixtures containing fewer by-products. The principal advantage of alcoholic solutions is complete homogeneity of the reaction mixture. By-products in the reaction 7 are the alcohol and ethyl ether corresponding to the halide undergoing reaction, in addition to higher amines. The formation of higher amines is suppressed by using a large excess of the aminating agent and by avoiding excessively long reaction times.
The amines were readily separated from the non-basic by-products by extraction of a benzene solution of all organic matter with dilute hydrochloric acid. The desired amine boiled sufficiently lower than the higher amines to allow separation in fairly pure form by careful distillation of a basic extraction mixture. Further purification was readily accomplished by recrystallization of the hydrochlorides. In the present work a large excess of ammonia (or methylamine) was employed and only small amounts of the higher amines were formed.
Primary chlorides generally gave better yields than did secondary chlorides. This is in accord with the observations of Cheronis 8, who studied the reaction rates of the four bromobutanes with alcoholic ammonia, and evaluated the yields therefrom.
The highest yields of amines were obtained from compounds having no substituent on the benzene ring. Moreover, the more labile the substituent, the lower was the yield. Thus fluoro derivatives gave better yields than did chloro derivatives, which in turn were more productive than bromo compounds. Yields were markedly lower in the amination of ortho substituted arylchloropropanes than in the case of para isomers.


1-Aryl-2-chloropropanes - The procedure for preparation of 2-chloro-1-(o-chlorophenyl)-propane and 2-chloro-1-(p-chlorophenyl)-propane is given as typical for this class of compounds. A mixture of 450 g (4.0 moles) of chlorobenzene and 32.4 g (0.2 mole) of anhydrous ferric chloride was cooled to -21C by an ice-salt-bath. Allyl chloride (76.5 g, 1.0 mole) was then added dropwise with stirring over a two-hour period. Stirring was continued for three hours longer. Meanwhile the temperature had risen to -16C. Hydrogen chloridewas evolved weakly throughout the entire reaction period. The mixture was shaken with about 1 kg of crushed ice and 100 mL of concentrated HCl. The organic layer was separated and washed with dilute HCl, and finally with distilled water. It was then filtered to remove a small amount of solid condensation product, and dried over anhydrous calcium sulfate.
The dried reaction mixture was distilled from a Claisen flask to effect a rough separation of unreacted materials, product, and tar. The fraction containing the products was carefully rectified at 10 mm pressure, using a 5-foot, glass-helices-packed column. A reflux ration of 25:1 was maintained. Two products, boiling at 103C at 10 mm and 111-112C at 10 mm, respectively, were obtained from the rectification. They yielded o-chlorobenzoic acid and p-chlorobenzoic acid, respectively, on permanganate oxidation. From the rectification curve and density data the yields were calculated to be 32% of 2-chloro-1-(o-chlorophenyl)-propane and 21% of 2-chloro-1-(p-chlorophenyl)-propane, or a total yield of 53% of products.
No allyl chloride was recovered from the reaction; however, rectification of the lower boiling fraction from the first distillation yielded, in addition to chlorobenzene, two compounds whose boiling points corresponded to 1,2-dichloropropane (9 g) and 1,3-dichloropropane (12 g). No attempt was made to prove their identity conclusively. Further distillation of the tarry residue from the reaction produced a viscous, slightly fluorescent oil (bp 133-135C at 2 mm), consisting of bis-(chlorophenyl)-propanes (10-12% yield). The remainder of the material was non-distillable tar. [...]

Ammonolysis of chloro compounds to primary amines - The preparation of benzedrine is typical of the method used for synthesis of the primary amines listed in Table II. Twenty-five grams (0.16 mole) of 2-chloro-1-phenylpropane was dissolved in 450 mL of saturated alcoholic ammonia solution (125 g/L) and sealed in an iron-pipe autoclave. The autoclave was mechanically rocked and was heated by an electric resistance winding. The charge was heated at about 160C for nine hours. It was then allowed to cool and filtered. The alcohol and excess ammonia were distilled, and the residue was made strongly basic with 6 M NaOH. The basic mixture was extracted four to five times with 20 mL portions of benzene, and the qaueous residue was discarded. The benzene solution was next extracted three to four times with 15 mL portions of 6 M HCl to secure the amine as a solution of its HCl. The aqueous acid solution was made basic with NaOH and extracted several times with benzene. The latter benzene solution was dried over anhydrous potassium carbonated. This benzene solution was distilled from a Claisen flask giving 11.1 g of benzedrine boiling at 80-82C at 11 mm. The yield was 51%.

Ammonolysis of chloro compounds to secondary methylamines - The technique for preparing the N-methylamines listed in Table II was identical to that used fro synthesis of the primary amines, except that an alcoholic solution of methylamine (204 g per liter) was used as the aminating agent.

2-chloro-1-(p-chlorophenyl)-propane 21 111-112C, 10
2-chloro-1-(o-chlorophenyl)-propane 32 103C, 10
2-chloro-1-phenylpropane 32 80-81C, 10
1-chloro-2-phenylpropane 20 82-83C, 10

Table I: Arylchloropropanes from allyl chloride.

1-phenyl-2- 51 80-82C, 11
2-phenyl-1- 51 81-83C, 10
N-methyl-2-phenyl-1- 62 95-96C, 15
N-methyl-1-phenyl-2- 44 98-100C, 20

Table II: Amines by ammonolysis of chlorides

[7] Clark et al. Patent US2183499
[8] Cheronis. Trans Illinois State Acad Sci 31 (1938) 126 [CA 33 (1939) 6792]

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