2-Phenylethylamines

From Biosynthesis to Total Synthesis Strategies and Tactics for Natural Products, First Edition. Edited by Alexandres L. Zografos. 2016 John Wiley Sons, Inc. Published 2016 by John Wiley Sons, Inc. 

FIGURE 12.1 Classification of tyrosine-derived secondary metabolites. 

E7 Catechol O-methyl transferase (COMT) E8 Guaiacol O-methyl transferase (GOMT) E9 Dopamine p-mono oxygenase ElO Phenylethanolamine N-methyl transferase 

Dopamine (4) serves as key intermediate in the biosynthesis of the stress hormone adrenaline (7). Two different routes are available for the biosynthesis of 4 from tyrosine (1). Hydroxylation of the aromatic ring, catalyzed by tyrosine hydroxylase, affords l-DOPA (2), which is converted to dopamine (4) via a decarboxylation step. Alternatively, tyrosine decarboxylase-mediated decarboxylation of tyrosine delivers tyramine that can be hydroxylated to afford the important bioactive intermediate 4. Hydroxylation of the benzylic position in 4 then leads to the formation of norepinephrine, also known as noradrenaline (6), which upon methylation of the amine is converted to epinephrine (adrenaline, 7) [1]. 

Phenylethylamines and catecholamines are of crucial importance for many physiological processes [2]. l-DOPA (2) serves as precursor for dopamine, which acts as neurotransmitter in the human brain. Dopamine is associated with reward-motivated behavior and cognitive alertness, and the compound is linked to controlling the release of other important hormones. In contrast to dopamine (4), l-DOPA is able to cross the blood-brain barrier, and it is used to increase the concentration of dopamine in the brain in patients suffering from Parkinson s disease [3]. 

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Aldehydes and ketones may be converted into the corresponding primary amines by reduction of their oximes or hydrazones (p. 93). A method of more limited application, known as the Leuckart Reaction, consists of heating the carbonyl compound with ammonium formate, whereby the formyLamino derivative is formed, and can be readily hydrolysed by acids to the amine. Thus acetophenone gives the i-phenylethylformamide, which without isolation can be hydrolysed to i-phenylethylamine. 

P-Phenylethylamine is conveniently prepared by the hydrogenation under pressure of benzyl cyanide with Raney nickel catalyst (see Section VI,5) in the presence of either a saturated solution of dry ammonia in anhydrous methyl alcohol or of liquid ammonia the latter are added to suppress the formation of the secondary amine, di- P phenylethylamine ... 

P-Phenylethylamine. Prepare p-phenylethyl phthalimide as above by substituting P phenylethyl bromide (Section 111,37) for benzyl... 

It is of interest to note that reduction of p-nitrostyrene with lithium aluminium hydride (compare Section VI, 10) gives p-phenylethylamine CgHgCHjCHjNHj. 

An example of the application of the Raney nickel catalyst is given in Section IV,35 (p-phenylethylamine from benzyl cyanide). 

In the resolution of 1 phenylethylamine using (-) malic acid the compound obtained by recrystallization of the mixture of diastereomeric salts is (/ )... 

Isobutylamine and 2 phenylethylamine can be prepared by the Gabriel synthesis ten butyl amine N methylbenzylamine and aniline cannot... 

Deamination, Transamination. Two kiads of deamination that have been observed are hydrolytic, eg, the conversion of L-tyrosiae to 4-hydroxyphenyUactic acid ia 90% yield (86), and oxidative (12,87,88), eg, isoguanine to xanthine and formycia A to formycia B. Transaminases have been developed as biocatalysts for the synthetic production of chiral amines and the resolution of racemic amines (89). The reaction possibiUties are illustrated for the stereospecific synthesis of (T)-a-phenylethylamine [98-84-0] (ee of 99%) (40) from (41) by an (5)-aminotransferase or by the resolution of the racemic amine (42) by an (R)-aminotransferase. 

Under alkaline conditions, an amine addition reaction can occur. For example, in the reaction of C3H3CH2CH2NH2 and aEyl alcohol in the presence of sodium alcoholate at 108°C for 80 h, 43.4% A/-(3-hydroxypropyl)phenylethylamine is formed (12). 

Venlafaxine (48) is a stmcturaHy novel phenylethylamine derivative that strongly inhibits both noradrenaline and serotonin reuptake. It lacks anticholinergic, antihistaminergic, and antiadrenergic side effects. As compared to placebo, most common adverse events are nausea, somnolence, dizziness, dry mouth, and sweating. Venlafaxine-treated patients also experienced more headaches and nausea, but less dry mouth, dizziness, and tremor than patients treated with comparator antidepressants. 

MAO is known to occur in at least two forms, MAO A and MAO B, based on substrate selectivity, inhibition by various dmgs, and cloning experiments. Clorgyline [17780-72-2] is a specific inhibitor of MAO A, which displays a substrate specificity for NE and serotonin. Deprenyl [2323-36-6] is a selective inhibitor of MAO B, and displays a substrate preference for P-phenylethylamine and benzyl amine. Dopamine and tyramine are substrates for both enzymes. 

Diaziridine (33) was obtained with more than 90% optical purity by separation of the a-phenylethylamine salts (76IZV1898). 

The present procedure was developed from those of Wallach and Freylon, based upon the general method discovered by Leuckart. a-Phenylethylamine also can be prepared satisfactorily by the reduction of acetophenone oxime with sodium and absolute alcohol or sodium amalgam, but the reagents are more expensive and the processes less convenient. The amine has been obtained by reducing acetophenone oxime electro-lytically, by reducing acetophenone phenylhydrazone with sodium amalgam and acetic acid, from a-phenylethyl bromide and hexamethylenetetramine, and by the action of methyl-magnesium iodide upon hydrobenzamide, as well as by other methods of no preparative value. 

The purity of (/-a-phenylethylamine-/-malate is not readily determined by its melting point or specific rotation, but rather by its massive crystalline form and solubility. The acid and neutral /-base-/-acid salts are much more soluble, and usually do not crystallize at all. 

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