Hydrogenolysis benzylamine

Nickel in the presence of ammonia is often used for reduction of nitriles to primary amines. The reaction is done at elevated temperatures and pressures ( 100 C, 1000 psig) unless massive amounts of nickel are used. Cobalt is used similarly but mainly under even more vigorous conditions. Nitriles containing a benzylamine can be reduced over Raney nickel to an amine without hydrogenolysis of the benzyl group (7). A solution of butoxycarbonyl)-3-aminopropyl]-N-<3-cyanopropyl)benzylamine (13.6 g) in 100 ml of ethanol containing 4 g. NaOH was reduced over 3.0 g Raney nickel at 40 psig for 28 h. The yield of A/ -benzyl-Air -(f-butoxycarbonyl)s >ermidine was 95% (7). 

Benzylamines tend to undergo hydrogenolysis with inversion over both Raney nickel and palladium, unlike benzyl-oxygen compounds I2Ia,I67o). 

Reductive animation of aromatic aldehydes to give benzylamines is accomplished by heating the aldehyde and tritylamine with molecular sieves, followed by the addition of sodium cyanoborohydride. Catalytic hydrogenolysis of the products with palladium on charcoal yields the benzylamines (equation 56)167. 

These amino alcohols can be prepared by disubstitution of the benzylamine with a suitable halogenated or sulfonated derivative of the alcohol, followed by debenzylation (hydrogenolysis) using H2. 

The clinical and commercial success of the antidepressant compound fluoxetine (Chapter 2 Prozac) engendered considerable work in other laboratories. A benzo-dioxan based compound that shows similar activity shares only a few stmctural features with the prototype. The benzodioxan nucleus (68-3) is formed by an alkylation reaction between the fluorocatechol (68-1) and the derivative (68-2) from meso, and hence achiral, butanetetrol. The benzyl protecting groups are then removed by hydrogenation over palladium, and the thus-obtained diol is converted to the fiii-toluene-sulfonate (68-4) by reaction with toluenesulfonyl chloride. Treatment of that intermediate with benzylamine leads to fiw-alkylation on the same nitrogen to form a pyrrolidine ring and thus the tricyclic compound (68-5). A second hydrogenolysis step then leads to fluparoxan (68-6) [70]. 

The optical isomers of DOM have been prepared in two ways. The racemic base has been resolved as the ortho-nitrotartranilic acid salt by recrystallization from EtOH. The (+) acid provides the (+) or S isomer of DOM preferentially. Also, the above-mentioned l-(2,5-dimethoxy-4-methylphenyl)-2-propanone can be reductively aminated with optically active alpha-methyl benzylamine with Raney Nickel. This amine is isolated and purified by recrystallization of the hydrochloride salt. When optically pure, the benzyl group was removed by hydrogenolysis with palladium on carbon. The mp of either of the optical isomers, as the hydrochloride salts, was 204-205 °C. 

Displacement reactions are rarely used for the preparation of amines as poly-alkylation reduces yields and makes product mixtures more complex. However, reaction of primary amines with primary and secondary sulfonates can provide good yields of monoalkylated product if care is taken to control the conditions and mode of addition. Benzylamine is particularly common as a primary amine nucleophile since the benzyl group can be removed by hydrogenolysis to give a primary amine. 

Derivatives of 14-hydroxydihydrocodeinone have been converted into 6a- and 6/ff-amino-compounds by condensation with benzylamine and then reduction and hydrogenolysis of the resulting Schiff-bases,195 and also into their hydrazones.196 Codeine and ethylmorphine have been nitrated and sulphonated at position 1197 and fluoro-compounds of structures (103 R = H), (103 R = OH), (104 R = H), and (104 R = OH) have been prepared from dihydrocodeinone and 14-hydroxy-dihydrocodeinone by treatment with diethylaminosulphur trifluoride.198... 

Lee described a strategy where benzylamine could be used as an ammonia equivalent as well [90]. The double reaction of the ditriflate below, followed by hydrogenolysis, furnished the desired ligand precursor in 69% yield over two steps, Eq. (135). The diamine product was also produced by double amination of the corresponding dibromide. 

Similarly, (S)-fi-tyrosine hydrochloride is prepared by addition of the lithium amide of N-[(R)-l-phenylethyl]benzylamine to methyl ( )-3-[(4-benzyloxy)phenyl]-2-propenoate and subsequent hydrogenolysis and saponification24. Recently, a number of publications concerning related work has appeared139-146. The reaction of lithiated, mono-silylated 1-phenylethyl-amines with a-enones has also been studied130131. 

Amino acids can be synthesized via the coupling of Schiff bases with carbanions generated by reduction of benzyl halides [143,144]. Electrolysis of benzyl chloride at mercury in DMF containing TBABr, and in the presence of the Schiff base formed from benzylamine and benzyl pyruvate, affords or-methylphenylalanine in up to 86% yield (after hydrogenolysis over palladium-charcoal). An antihypertensive agent, or-methyl-j6-(3,4-dihydroxyphenyl)alanine, has been prepared by reductive coupling of the aforementioned Schiff base with 3,4-methylenedioxybenzyl chloride. 

The nonpyrophoric PdfOHjj/C (Pearlman s catalyst) catalyzes the selective hydrogenolysis of benzylamines in the presence of benzyl ethers. ... 

Reductive amination. Reductive amination of 3-ketosteroids with ammonia, hydrogen, and Pd-C gives 3)3-aminosteroids, but in poor yield. It is preferable to use benzylamine the intermediate secondary amine undergoes hydrogenolysis. The reaction is selective for 3-ketosteroids carbonyl functions at C17 and Cm are not affected. Thus hydrogenation of progesterone in the presence of benzylamine and Pd-C afforded 3/3-amino-5)3-pregnane-20-one in 71% yield. 

Another route to amine ID used the isomerically-mixed 1,2-cyclopropanedicarboxylic acid 2. directly without recourse to the anhydride D. Thus, ca. one mole of crude acid 2. was treated with benzylamine at 180°C to afford a crystalline sample of impure imide D (72%). Nevertheless, when this impure material was reduced with lithium aluminum hydride, the amine D (68%) was isolated by distillation in a high state of purity. As before, catalytic hydrogenolysis of the N-benzyl group led to a quantitative yield of the bicyclic amine hydrochloride ID. In this... 

---