by Gordon A. Alles, JACS 54, 271-274 (1932)

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In a previous paper (1) it was demonstrated with dl-beta-phenylisopropylamine that the introduction of a methyl group into the side chain of beta-phenyl-ethylamine furnishes a compound differing from the latter with regard to certain of its effects when administered as a drug compound. The dl-beta phenylisopropylamine exerts a pressor effect for a longer period of time and is quite effective after oral administration.

The syntheses of the parent dl-beta-phenylisopropylamine and the desired methoxy derivative are reported in this paper; the physiological studies of the compounds prepared will be reported in another place.

The synthesis of beta-phenylethylamines is often accomplished, especially for proof of structure, by condensing an aromatic aldehyde with nitromethane under suitable conditions and complete reduction of the beta-nitrostyrene so formed, to the hydrogenated amine derivative. It was found that a similar preparative process can be carried out with nitroethane in place of nitromethane, the resultant product being a dl-beta-phenylisopropylamine.

The initial condensation step in the process was found to be most simply carried out by the method of Knoevenagel and Walther (3). The second step, the complete reduction, involves considerable difficulty but the described electrolytic reduction method gives fair yields of the desired amines while
several attempts at catalytic hydrogenation or reduction with various metals or their amalgams were not at all successful.

Experimental Part

The details of preparation of the dl-beta-phenylisopropylamine and its 4-methoxy derivative differ only in the aldehyde used and the intermediate and final products isolated.

Condensation of Aldehyde and Nitroethane

0.2 Mole of aldehyde, 0.2 mole of nitroethane and 0.02 mole of n-amylamine were mixed and set aside at room temperature in the dark. After a day water began to separate from the mixture; after several days the mixture became quite solid. After two weeks, the mixture was dissolved to a homogeneous
solution by warming with 50 ml of ethanol and then on cooling a fine crystal product was obtained. From benzaldehyde, 0.15 mole of phenylnitro-propylene melting at 65-66°C was obtained. The melting point of this compound has been reported as 64°C (2). From anisaldehyde, 0.15 mole of 4-methoxyphenylnitropropylene melting at 43-44°C was obtained. The melting point of this compound has been reported as 48°C (3).

Reduction of Phenylnitropropylenes

0.1 Mole of phenylnitropropylene dissolved in a catholyte of 100 ml of ethanol, 50 ml of acetic acid and 50 ml of 12 N sulfuric acid was placed above a 40 cm2 mercury cathode in a porous cell surrounded by a 3 N sulfuric acid anolyte with a water-cooled lead anode. Four amperes was passed for twenty hours and the temperature in the catholyte was kept between 30-40°C.

The resultant catholyte was partially evaporated, then made strongly alkaline and the separated basic layer taken up with benzene. The desired amine was then extracted from the benzene by just neutralizing with dilute hydrochloric acid and separating the aqueous layer. This was then evaporated
and the product crystallized. From phenylnitropropylene, 0.02 mole of dl-beta-phenylisopropylamine hydrochloride melting at 144-145°C was obtained. The melting point of this compound has been reported as 145-147°C (4). From 4-methoxy-phenylnitropropylene, 0.02 mole of dl-beta-4-methoxyphenylisopropyl-amine hydrochloride melting at 205-209°C was obtained. The melting point of
this compound has bees reported as 210°C (2).


[1] Piness, Miller and Alles, J. Am. Med. Assn. 94, 790 (1930)
[2] Mannich and Jacobsohn, Ber. 43, 189 (1910)
[3] Knoevenagel and Walther, Ber. 37, 4502 (1904)
[4] Hey, J. Chem. Soc. 18 (1930)


Constitution of ephedrine. Desoxyephedrine.

A. Ogata, J. Pharm. Soc. Japan 451, 751-54 (1919), CA 14, 745 (1920)

Ephedrine was discovered in Ephedra vulgaris by Prof. Nagai. It is known to contain a Ph nucleus, a side chain with 3 C atoms, an OH and a NHMe group. The main point of uncertainty is the positions where the OH and NHMe groups are linked. The 6 possibilities are PhCH(OH)CHMeNHMe (A), PhCH(NHMe)CHMeOH (B), PhCH(OH)CH2CH2NHMe (C), PhCH(NHMe)CH2CH2OH (D), PhCH2CH(OH)CH2NHMe (E), and PhCH2CH(NHMe)CH2OH (F).

Through a study of the structure of desoxyephedrine, O. attempts to show that A is the correct formula for ephedrine. From the work of E. Smidt, Miller, Bumming, and Nagai, O. concludes that the OH is linked to the Ph group. If NHMe is linked at the last C, the removal of OH from ephedrine
ought to produce optically inactive desoxyephedrine but the fact is the resulting product is dextrorotatory. If it is at the next to the last C atom, then the resulting compound should be identical with synthetic phenylisopropylmethylamine. O. has prepared desoxyephedrine by reducing the condensation product of PhCH2COMe and MeNH2.

To 100 g of alcoholic MeNH2, 40 g. of phenylacetone is added and left at room temp. for 4 weeks in a stoppered bottle. Then 150 g. of alcohol is added, and 30 g of Na is used for reduction, collecting the large amount of MeNH2 in HCI. After the reduction, H2O is added, the excess of alcohol is
evaporated off, steam distillation is conducted till the distillate is no longer alkaline. HCI is used for neutralization. The insoluble portion is extracted with ether and the extract is concentrated and precipitated with HgCl2. The Hg salt is decomposed with H2S, giving 15 g of the HCl salt. After purification with alcohol, plate-shaped crystals are obtained with a mp of 134-5°C. The free base, which has an amine odor, is a liquid and has a bp of 209-210°C and 93°C at 15 mmHg.

In all respects, this product is very similar to phenylisopropylamine obtained by Nagai by reducing ephedrine and its analysis shows it to be C10H15N. Separation of the d- from the l-form was accomplished easily by the tartaric acid method. The further characteristics of the different isomers are as follows:

dl form: bp 209-210°C, HCl salt mp 131-5°C.
d form: bp 208-210°C, HCl salt mp 170-175°C)
l form: bp 210°C, HCl salt mp 170-171°C.