IS - 1-phenylethylamine

Whenever possible, the chemical reactions involved in the formation of diastereomers and their conversion to separate enantiomers are simple acid-base reactions. For example, naturally occurring (S)-(-)-malic acid is often used to resolve amines. One such amine that has been resolved in this way is 1-phenylethylamine. Amines are bases, and malic acid is an acid. Proton transfer from (S)-(-)-malic acid to a racemic mixture of (/ )- and (5)-1-phenylethylamine gives a mixture of diastereomeric salts. 

Neither ll NMR spectrum is consistent with /V-mcthylbenzylaminc, which would have two singlets due to the methyl and methylene groups. Likewise, the spectra are not consistent with /V-cthylanilinc, which would exhibit the characteristic triplet-quartet pattern of an ethyl group. Although a quartet occurs in the spectrum of compound A, it corresponds to only one proton, not the two that an ethyl group requires. The one-proton quartet in compound A arises from an H—C—CH3 unit. Compound A is 1-phenylethylamine. 

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

In the resolution of 1-phenylethylamine using (-)-malic acid, the compound obtained by recrystallization of the mixture of diastereomeric salts is (/ )-1-phenylethylammonium (S)-malate. The other component of the mixture is more soluble and remains in solution. What is the configuration of the more soluble salt ... 

To a mixture of 1,115 parts dl-1 -phenylethylamine and 950 parts dimethylformamide are added successively 655 parts triethylamine and 1,130 parts ethyl chloroacetate. After the addition is complete, the whole Is stirred overnight. Then there are added 5,600 parts anhydrous ether and the whole is filtered. 

The filtrate is washed four times with water, dried and evaporated, yielding dl-N-[ (ethoxy-carbonyDmethyl] -1 -phenylethylamine. This residue is dissolved in 4 00 parts xylene while refluxing and to this solution are added 450 parts formic acid. After boiling for a few hours, the mixture is cooled and washed successively three times with a 20%solution of formic acid, water, sodium hydrogen carbonate solution. 

The organic layer is then dried, filtered and evaporated. The oily residue is distilled in vacuo, yielding 1,600 parts dl-N-formyI-N-[(ethoxycarbonyl)methyl] -1 -phenylethylamine (boiling point 160°C to 170°Cat 0.8 mm pressure). 30 parts of a sodium dispersion, 50% in paraffin oil are added to 450 parts tetrahydrofuran and the whole is slowly heated to a temperature of 40°C, while stirring. While maintaining this temperature (cooiing on a water bath is necessary) there are added portionwise 30 parts ethanol. 

After the addition is complete, the whole Is cooled on an ice bath and there is added drop-wise a solution of 144 parts dl-N-formyl-N-[(ethoxycarbonyl)methyl] -1-phenylethylamine in 133 parts ethyl formate. After the addition is complete, the mixture is stirred overnight at room temperature. 

Racemization of amines is difficult to achieve and usually requires harsh reaction conditions. Reetz et al. developed the first example of DKR of amines using palladium on carbon for the racemization and CALB for the enzymatic resolution [35]. This combination required long reaction times (8 days) to obtain 64% yield in the DKR of 1-phenylethylamine. More recently, Backvall et al. synthesized a novel Shvo-type ruthenium complex (S) that in combination with CALB made it possible to perform DKR of a variety of primary amines with excellent yields and enantioselectivities (Figure 4.13) [36]. 

The DKR of amine is more challenging compared to that of secondary alcohol since no metal catalysts have been known for the efficient racemizahon of amine. Reetz et al. reported for the first time the DKR of amine, in which 1-phenylethylamine was resolved by the combination of lipase and palladium (Scheme 4). In this procedure, CALB and Pd/C were employed as the combo catalysts. However, the DKR required a very long reaction time (8 days) at 50-55°C and provided a poor isolated yield (60%). Recently, an improved procedure using Pd on alkaline earth salts as the racemizahon catalyst was reported by Jacobs et al. " The DKR reachons were performed at 70°C for 24-72 h and 75-88% yields were obtained with 99% or greater enanhomeric excess. 

The stereochemistries of the reactions between 0-aryl 0-methyl phosphonochloridothioates and nucleophiles have been studied in relation to the synthesis of 1,3,2-oxazaphospholidines. No displacement of chlorine takes place on treatment of O-methyl 0-4-nitrophenyl phosphonochloridothioate with 2-methoxyethanol, and in the presence of 1-phenylethylamine, it is only the latter which reacts. In addition, when the same phosphonochloridothioate is treated with sodium ethoxide, it is the 4-nitrophenoxy group, rather than chlorine, which is displaced. Both displacements were shown to occur with inversion of configuration at phosphorus. The use of such an acid chloride as a two-step 1cyclophosphorylating1 agent of 2-aminoalcohols to give 1,3,2-oxazaphospholidines (209), is illustrated. ... 

It is important to mention again at this point that a general feature of the solid-state ionic chiral auxiliary approach to asymmetric synthesis is that not all chiral auxiliaries lead to high enantiomeric excesses. A case in point is found in the work of Natarajan et al. on the a-oxoamide-containing salts 43 (Scheme 10) [29]. Like the nonionic a-oxoamides discussed previously (Sect. 2.2), these compounds undergo photocyclization to p-lactam derivatives, and while the prolinamide salt behaves perfectly, leading to p-lactam 44 in 99% ee at 99% conversion, the corresponding 1-phenylethylamine salt affords nearly racemic photoproduct (3% ee at 99% conversion). The reason for this difference is... 

Fig. 8.3 Lipase-catalyzed formation of 2-methoxy-/V-[(7/ )-l-phenylethyl]-acetamide (III) and fSj-phenylethylamine (IV). The reaction uses racemic 1-phenylethylamine (I) and ethylmethoxyacetate (II) as educts and is carried out in methyl-tert-butylether. As a byproduct, ethanol is formed.

Preparative scale reduction of oximes at a mercury or lead cathode in acid solution has been used in the conversion of the carbonyl function to amine. Originally, 30-50% sulphuric acid was used as solvent [195] but ethanol with dilute hydrochloric acid is usually satisfactory. Aliphatic and aromatic oximes give amines in 64-86% yields [196]. Aromatic ketoximes are also reducible in alkaline solution and acetophenone oxime has been converted to 1-phenylethylamine in a tri-potassium orthophosphate solution [197], The reduction of oximes in acid solution is tolerant of many other substituents as indicated by a number of examples [198, 199, 200. Phenylglyoxa monoxime in acid solution is however reduced at both the carbonyl and the oxime centres by sodium amalgam to yield 2-amino-1-phenylethanol [201]... 

The piperazin-2,5-dione 6 is easily prepared from (5)-1 -phenylethylamine and chloroacetyl chloride in a two-step sequence5 6. Base-induced enolization followed by alkylation6 furnishes an easily separable mixture of diastereomers 7 and 8 in 90- 95 % yield with d.r. 55 45 to 90 10 7. 

This Mulheim chemistry has been highlighted by the discovery of the highly enantioselective hydrovinylation of styrene to produce chiral 2-phenyl-1-butene in 95.2% ee for a 10 kg-scale reaction (Scheme 60) (132). The Ni catalyst is very reactive and contains the unique chiral dimeric aminophosphine ligand derived from (R)-myrtenal and (S)-1-phenylethylamine. Computer simulations suggest that in this chiral Ni complex, the phenyl substituent of the chiral phenylethyl group acts as a windshield wiper across the catalytically active metal center. This... 

An efficient method has been reported478,479 for the asymmetric synthesis of chiral 1-arylethylamines. The method is the reductive amination with optically active 1-phenylethylamine of substituted acetophenones via the corresponding imines (equation 52). 

A major variation is the use of formic acid or one of its derivatives as the reductant (the Leuckart reaction). In the synthesis of 1-phenylethylamine (Expt 5.197), ammonium formate is heated with aceptophenone while the water formed in the reaction is carefully removed by fractional distillation to give the required amine as its N-formyl derivative, (l-phenylethyl)formamide. This is then hydrolysed with acid to yield the primary amine. The procedure has been satisfactorily applied to many aliphatic-aromatic, alicyclic and aliphatic-heterocyclic ketones, some aromatic ketones and aldehydes, and to some aliphatic aldehydes and ketones boiling at about 100 °C or higher. 

The procedure is illustrated in Expt 5.219 by the resolution of ( )-a-methyl-benzylamine (1-phenylethylamine) with the aid of tartaric acid. 

The more soluble salt must have the opposite configuration at the stereogenic center of 1-phenylethylamine, that is, the S configuration. The malic acid used in the resolution is a single enantiomer, S. In this particular case the more soluble salt is therefore (S)-l-phenylethylammonium (5)-malate. 

It is widely known that 1-phenylethylamine (PEA) can be resolved with enantiopure mandelic acid (MA) via diastereomeric salt formation in industrial-scale production. However, the optical purity of PEA obtained was not stable (97-99% ee) whereas more than 99% ee has been steadily obtained in a laboratory. 

Despite the results obtained by Emmenegger123 showing that one chelate ring placed in the equatorial plane of the complex may be opened quite easily in a reaction with a monodentate ligand, it seems that the strain of this chelate ring is smaller in complexes of penten compared to EDTA. Contrary to the result with [Ni(PDTA)]2-, it was not possible to coordinate 1-phenylethylamine in a stereoselective way with [Ni((R)-mepenten)]2+113 124. ... 

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