Nitriles, catalytic hydrogenation amines

In catalytic hydrogenation, a compound is reduced with molecular hydrogen in the presence of a catalyst. This reaction has found appHcations in many areas of chemistry including the preparation of amines. Nitro, nitroso, hydroxylamino, azoxy, azo, and hydrazo compounds can all be reduced to amines by catalytic hydrogenation under the right conditions. Nitriles, amides, thioamides, and oximes can also be hydrogenated to give amines (1). Some examples of these reactions foUow ... 

Nitrile Intermediates. Most quaternary ammonium compounds are produced from fatty nitriles (qv), which are ia turn made from a natural fat or oil-derived fatty acid and ammonia (qv) (Fig. 2) (see Fats AND FATTY oils) (225). The nitriles are then reduced to the amines. A variety of reduciag agents maybe used (226). Catalytic hydrogenation over a metal catalyst is the method most often used on a commercial scale (227). Formation of secondary and tertiary amine side-products can be hindered by the addition of acetic anhydride (228) or excess ammonia (229). In some cases secondary amines are the desired products. 

Catalytic hydrogenation of the nitrile function of cyanohydrins can give amines. As in the case of ordinary nitriles, catalytic reduction of cyanohydrins can yield a mixture of primary, secondary, and tertiary amines. Addition of acid or acetic anhydride to the reaction medium minimizes formation of secondary or tertiary amines through formation of the amine salt or acetamide derivative of the primary amine. 

Reduction of nitriles (Section 22.9) Nitriles are reduced to primary amines by lithium aluminum hydride or by catalytic hydrogenation. 

Aniline 77 was converted into its diazonium salt with nitrous acid and this was followed by reduction with stannous chloride to afford the corresponding arylhydrazine 78. Condensation of 78 with 3-cyanopropanal dimethylacetal 79 gave the arylhydrazone 80. Treatment of 80 with PPE resulted in cyclization to indole 81. The nitrile group was then reduced to the primary amine by catalytic hydrogenation. Reaction of the amine with excess formalin and sodium borohydride resulted in Imitrex (82). 

Catalytic hydrogenation of nitriles may result in several products primary, secondary, and tertiary amines imines hydrocarbons aldehydes amides and... 

Amination. A continuous process in which aliphatic and aromatic amines are produced by (1) high pressure, catalytic hydrogenation of nitro compounds (-NO2 or nitriles (-CN)) and (2) action of ammonia on a chloro- or hydroxy-compound. 

Nitriles on reduction with lithium aluminium hydride (LIAIH ) or catalytic hydrogenation produce primary amines. This reaction is used for ascent of amine series, i.e., for preparation of amines containing one carbon atom more than the starting amine. 

As a further illustration of the reactivity of the 3 position toward electrophiles, the methoxyindole (25-1) readily undergoes Mannich reaction with formaldehyde and dimethylamine to afford the aminomethylated derivative (25-2). Treatment of that intermediate with potassium cyanide leads to the displacement of dimethylamine and the formation of the nitrile (25-3), possibly by an elimination-addition sequence involving a 3-exomethylene-indolenine intermediate. The protons on the methylene group adjacent to the nitrile are quite acidic and readily removed. Reaction of (25-3) with methyl carbonate in the presence of sodium methoxide gives the carbo-methoxylated derivative (25-4). Catalytic hydrogenation leads to reduction of the nitrile to a primary amine. There is thus obtained the antihypertensive agent indorenate (25-5) [26]. 

Catalytic hydrogenation or LiAlH4 reduction of amides, azides or nitriles produces amines (see Section 5.7.23). 

Amides, azides and nitriles are reduced to amines by catalytic hydrogenation (H2/Pd—C or H2/Pt—C) as well as metal hydride reduction (LiAlH4). They are less reactive towards the metal hydride reduction, and cannot be reduced by NaBITj. Unlike the LiAlIU reduction of all other carboxylic acid derivatives, which affords 1° alcohols, the LiAlIU reduction of amides, azides and nitriles yields amines. Acid is not used in the work-up step, since amines are basic. Thus, hydrolytic work-up is employed to afford amines. When the nitrile group is reduced, an NH2 and an extra CH2 are introduced into the molecule. 

Lithium aluminum hydride in tetrahydrofuran has been found to reduce aromatic nitriles to give an amine and to give an imine which is formed from the addition of the amine to the nonisolatable imine intermediate followed by an elimination of ammonia [24] (Eq. 14). This is simpler than catalytic hydrogenation of nitriles [25], which gives poor yields of imines. 

CARBON SKELETON. The technique of precolumn catalytic hydrogenation can be applied to reduce certain unsaturated compounds to their parent hydrocarbons. Compounds analyzed by this technique include esters, ketones, aldehydes, amines, epoxides, nitriles, halides, sulfides, and fatty acids. Fatty acids usually give a hydrocarbon that, is the next lower homolag than the parent acid. For most systems utilizing hydrogenation, hydrogen is also used as the carrier gas. Usually 1% palladium or platinum on a non-adsorptive porous support such as AW-Chromosorb P is used as the catalytic packing material. 

The heterogeneous catalytic hydrogenation of nitriles has been used in amine preparation for a long time. Generally the products are a mixture of primary, secondary and tertiary amines, the nature of which depends on the catalyst used as well as on reaction conditions (refs. 1,2). The selectivity of nitrile hydrogenation is of importance, particularly in the production of primary amines. In such reactions the catalysts most often proposed are Raney nickel catalysts (refs. 1-3). 

In the course of the catalytic hydrogenation of a,us dinitriles over Raney nickel, by-products are obtained from C-N and C-C bond formation. The mechanism of the formation of these compounds was investigated. Cyclic and linear secondary amines can result from the same secondary imine through a transimination process involving a ring-chain tautomerism. Stereochemical results for 2-aminomethyl-cyclopentylamine (AMCPA) are in accordance with a specific cyclisation pathway favored by an intramolecular hydrogen bond giving rise to the cis isomer from aminocapro-nitrile, unfavored in the case of adiponitrile which leads to the trans AMCPA as the major isomer. 

Catalytic hydrogenation of nitriles over Raney nickel leads to primary amines with variable amounts of secondary and tertiary amines depending on reaction conditions (Ref. 1). These by-products result from hydrogenation of secondary imines and enamines respectively. 

Lithium aluminum hydride is a convenient reagent for reduction of nitro compounds, nitriles, amides, azides, and oximes to primary amines. Catalytic hydrogenation works also. Aromatic nitro compounds are reduced best by reaction of a metal and aqueous acid or with ammonium or sodium polysulfides (see Section 23-12B). Reduction of /V-substituted amides leads to secondary amines. 

Formation and Reduction of Nitriles Like the azide ion, cyanide ion (- C=N ) is a good Sn2 nucleophile it displaces leaving groups from unhindered primary and secondary alkyl halides and tosylates. The product is a nitrile (R—C=N), which has no tendency to react further. Nitriles are reduced to primary amines by lithium aluminum hydride or by catalytic hydrogenation. 

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