Phenylethylamine, from acetophenone

Even if the imine may not be isolated, the transient species may sometimes be trapped by reaction with a suitable nucleophile. This is the basis of the reductive amination reaction in which an amine is formed from the reaction of ammonia with a carbonyl compound in the presence of a reducing agent such as sodium borohydride or formate. Use of a primary or secondary amine results in the specific formation of secondary or tertiary amines respectively (Fig. 5-45). This synthetic method allows the preparation of high yields of amines, in contrast to the unselective and uncontrollable reaction of alkylating agents with amines. A specific example involving the preparation of a-phenylethylamine from acetophenone is presented in Fig. 5-46. 

The methods for preparation of a-phenylethylamine are reviewed in Org. Syn. Coll. Vol. 2, 1943, 506, where detailed directions are given for the preparation of this amine from acetophenone and ammonium formate. The procedure given above is based upon that of Schwoegler and Adkins.1... 

Many water-insoluble ketones, aliphatic, aryl aliphatic, and heterocyclic, respond favorably to treatment with ammonium formate or formamide to form with subsequent hydrolysis the primary amines. A typical procedure for the synthesis of a-phenylethylamine (66%) from acetophenone and ammonium formate has been applied to many other ketones (65-84%). Nuclear alkoxyl, halo, and nitro groups are not disturbed. The reaction with formamide as the reducing agent is catalyzed by ammonium formate, ammonium sulfate, or magnesium chloride. ... 

In addition to four component condensation, several other applications of chiral primary ferrocenylalkyl amines have been published. Thus, an asymmetric synthesis of alanine was developed (Fig. 4-3la), which forms an imine from 1-ferrocenylethyl amine and pyruvic acid, followed by catalytic reduction (Pd/C) to the amine. Cleavage of the auxiliary occurs readily by 2-mercaptoacetic acid, giving alanine in 61% ee and allowing for recycling of the chiral auxiliary from the sulfur derivative by the HgClj technique [165]. Enantioselective reduction of imines is not limited to pyruvic acid, but has recently also been applied to the imine with acetophenone, although the diastereoisomeric ferrocenylalkyl derivatives of phenylethylamine were obtained only in a ratio of about 2 1 (Fig. 4-31 b). The enantioselective addition of methyl lithium to the imine with benzaldehyde was of the same low selectivity [57]. Recycling of the chiral auxiliary was possible by treatment of the secondary amines with acetic acid/formaldehyde mixture that cleaved the phenylethylamine from the cation and substituted it for acetate. 

If the chiral amino alcohol is incorporated into polystyrene, a chiral polymeric reducing agent is obtained. Acetophenone O-methyloxime was reduced by such a polymeric borane complex to give optically active 1-phenylethylamine with 99% ee35 36 With borane-tetrahydrofuran and 1 mol% of the chiral amino alcohol (lS,3S,5S)-(a,a-diphenyl)hydroxymethyl-2-azabicy-clo[3.3.0]octane (7), (7 )-1-phenylethylamine can be synthesized from acetophenone O-methyloxime in 64% yield with 17% ee37. 

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. 

R)-a-Phenylalkylamines. (R)-a-Phenylethylamine (4) can be prepared in about 97% optical purity by addition of methylmagnesium bromide to the chiral hydrazone obtained from benzaldehyde and the N-amino derivative (1) of D-( —)-ephedrine followed by hydrogenolysis (equation I). Acetophenone is not a suitable starting material because it reacts with 1 to form two isomeric hydrazones. ... 

On the other hand, the diastereoselective reduction of the chiral hydrazone derived from V-aminoephedrine and acetophenone and subsequent hydrogenolysis affords (5)-a-phenylethylamine with 30% ee. Optically active a-phenylethylamine with high ee is obtained from the diastereoselective alkylation of chiral hydrazones derived from (/ )- or (S)-l-amino-2-(methoxymethyl)pyrrolidine. ... 

To improve upon the selectivity of the ketimine reduction process further, the hydrosilylation of a range of substrates derived from (/ )- -phenylethylamine were examined [37]. Optimization of the reaction conditions allowed obtaining complete diastereoselective reduction of a wide range of acetophenone-derived ketimines as well as a-imino esters, demonstrating the cooperative effect of catalyst and the (/ )-methyl benzyl residue at the imine nitrogen. In this context, we reported also a low cost protocol for a highly stereoselective reduction of ketimines bearing a very cheap and removable chiral auxiliary, promoted by an achiral inexpensive Lewis base, such as DMF [38]. 

Cassimjee et al. reported [22] that a variant engineered aminotransferase at TrpOOCys from Chromohacterium violaceum showed a 29-fold increase on spedfidty for synthesis of (S)-phenylethylamine and about fivefold on spedfidty for 4 -substituted acetophenones, where the groups at 4 position were bromo, chloro, hydroxy, methoxy, nitro, methyl, and cyano. The amine donor was isopropylamine. The reaction schemes are shown in Figure 7.5. 

---