Raney nickel reductive amination

ANILINES, BENZYL AMINES, AND ANALOGUES An orally active local anesthetic agent that can be used as an (intiarrhythmic agent is meobenti ne (57). Its patented synthesis starts with -hydroxyphenyl nitrile and proceeds by dimethyl sulfate etherification and Raney nickel reduction to Alkylation of -methyl-dimethylthiourea with completes l.he synthesis of meobenti ne (57). ... 

Scott Denmark of the University of Illinois reports (J. Org. Chem. 68 8015,2003) a hetero intramolecular Diel-Alder reaction of a nitro alkene 5, followed by intramolecular dipolar cycloaddition of the resulting nitronate 6, to give the tricycle 7. Raney nickel reduction effected cleavage of the N-0 bonds and reductive amination of the liberated aldehyde, to give, after acetylation, the angularly substituted cis-decalin 8. 

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. 

Thiazolecarboxylic acids, esters or acid chlorides react readily with ammonia or various amines, affording the corresponding carboxamides. Dehydration of the amides with phosphorus pentoxide or phosphoryl chloride occurs readily and gives the corresponding nitriles (Scheme 99). Thiazolecarboxylic acid hydrazides are obtained in a similar way, using hydrazine or substituted hydrazines instead of ammonia or amines. The Raney nickel reduction of cyanothiazoles leads to the corresponding amino compounds, the 4-cyano derivative being the isomer most readily reduced. 

Reductive N-N cleavage of hydrazines. A diastcreoselective synthesis of chiral a-amino aldehydes (4) from glyoxal involves an intermediate dimethylhydrazone (1), which reacts with an alkyllithium to provide an or-substituted N. N -dimcthylhydrazine (2). The mildest method for cleavage of hydrazines to primary amines (3) involves hydrogenolysis catalyzed by Raney nickel at 30-50. This Raney nickel reductive cleavage is markedly improved by sonication and proceeds at atmospheric pressure of H2 at 20 in CHjOH in yields of 66-84% with no raccmization or debenyzlation.1... 

In this domino process, first, the nitro group gets reduced to give an amine moiety, which then undergoes a Michael addition to afford an unsaturated ester the final step is the elimination of water to yield 117 [69]. Recently, Banwell et al. applied a domino nitroarene reduction protocol for the total synthesis of 1,5-methanoazocino[4,3-f)]indole 118 framework of the uleine and strychnos alkaloids (Scheme 9.24). Pd/C reduction of nitroarene 119 in methanolic solution afforded annulated indole 120, which presumably arose from the reduction of both nitro and the carbon-carbon double bond. Raney-nickel reduction produced the amine analog 121. However, Raney-cobalt reduction resulted in the tetracyclic compound... 

The zwitterion (6) can react with protic solvents to produce a variety of products. Reaction with water yields a transient hydroperoxy alcohol (10) that can dehydrate to a carboxyUc acid or spHt out H2O2 to form a carbonyl compound (aldehyde or ketone, R2CO). In alcohoHc media, the product is an isolable hydroperoxy ether (11) that can be hydrolyzed or reduced (with (CH O) or (CH2)2S) to a carbonyl compound. Reductive amination of (11) over Raney nickel produces amides and amines (64). Reaction of the zwitterion with a carboxyUc acid to form a hydroperoxy ester (12) is commercially important because it can be oxidized to other acids, RCOOH and R COOH. Reaction of zwitterion with HCN produces a-hydroxy nitriles that can be hydrolyzed to a-hydroxy carboxyUc acids. Carboxylates are obtained with H2O2/OH (65). The zwitterion can be reduced during the course of the reaction by tetracyanoethylene to produce its epoxide (66). 

Reduction. Just as aromatic amine oxides are resistant to the foregoing decomposition reactions, they are more resistant than ahphatic amine oxides to reduction. Ahphatic amine oxides are readily reduced to tertiary amines by sulfurous acid at room temperature in contrast, few aromatic amine oxides can be reduced under these conditions. The ahphatic amine oxides can also be reduced by catalytic hydrogenation (27), with 2inc in acid, or with staimous chloride (28). For the aromatic amine oxides, catalytic hydrogenation with Raney nickel is a fairly general means of deoxygenation (29). Iron in acetic acid (30), phosphoms trichloride (31), and titanium trichloride (32) are also widely used systems for deoxygenation of aromatic amine oxides. 

Ethylamines. Mono-, di-, and triethylamines, produced by catalytic reaction of ethanol with ammonia (330), are a significant outlet for ethanol. The vapor-phase continuous process takes place at 1.38 MPa (13.6 atm) and 150—220°C over a nickel catalyst supported on alumina, siUca, or sihca—alumina. In this reductive amination under a hydrogen atmosphere, the ratio of the mono-, di-, and triethylamine product can be controlled by recycling the unwanted products. Other catalysts used include phosphoric acid and derivatives, copper and iron chlorides, sulfates, and oxides in the presence of acids or alkaline salts (331). Piperidine can be ethylated with ethanol in the presence of Raney nickel catalyst at 200°C and 10.3 MPa (102 atm), to give W-ethylpiperidine [766-09-6] (332). 

Nickel compounds Hydrogenations (e.g. Raney nickel) Conversion of synthesis gas to methane Reduction of organo nitro compounds to amines Carcinogenic (nickel subsulphide). Skin sensitization... 

The use of primary amines instead of ammonia affords l,2-dialkyl-/l -pyrrolines or l,2-dialkyl-/l -piperideines. Amino ketones with a primary amino group are intermediates in the reduction of y-nitropropylalkyl ketones (14,15) or S-nitrobutylalkyl ketones (16-18) by catalytic hydrogenation over Raney nickel or with zinc and hydrochloric acid (Scheme 1). 

Two different sets of experimental conditions have been used. Buu-Hoi et al. and Hansen have employed the method introduced by Papa et using Raney nickel alloy directly for the desulfurization in an alkaline medium. Under these conditions most functional groups are removed and this method is most convenient for the preparation of aliphatic acids. The other method uses Raney nickel catalysts of different reactivity in various solvents such as aqueous ammonia, alcohol, ether, or acetone. The solvent and activity of the catalyst can have an appreciable influence on yields and types of compounds formed, but have not yet been investigated in detail. In acetic anhydride, for instance, desulfurization of thiophenes does not occur and these reaction conditions have been employed for reductive acetylation of nitrothiophenes. Even under the mildest conditions, all double bonds are hydrogenated and all halogens removed. Nitro and oxime groups are reduced to amines. 

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). 

A solution of 151 grams of 1-(3, 4 -dimethoxyphenyl)-2-propanone oxime in 200 cc of absolute ethanol is treated with 5 grams of Raney nickel catalyst and ammonia in an autoclave at about 25 atm of pressure and at 75 -100°C. The reduction is complete in about one-half hour and the reaction mixture is filtered and fractionated under reduced pressure to recover the a-methylhomoveratrylamine formed by the reduction. a-Methylhomoveratryl-amine thus prepared boiled at 163°-165°C at 18 mm pressure. 

Complete reduction of the azepine ring to hexahydroazepine has been effected with hydrogen and palladium,40 or platinum,135 239 catalysts. For example, ethyl 1 f/-azepine-l-carboxylate is reduced quantitatively at room temperature to ethyl hexahydroazepine-l-carboxylate (92% bp 118 —120 3C).134 136 TV-Phenyl-S/Z-azepin -amine (1), however, with platinum(IV) oxide and hydrogen in methanol yields the hexahydroazepine 2 in which the amidine unit is preserved in the final product.34 The same result is obtained using 5% palladium/barium carbonate, or 2 % palladium/Raney nickel, as catalyst. 

Under more forcing conditions (Raney nickel, MeOH, H2 pressure, 150°C, 6h). 3H-azepin-2-amine undergoes reductive deamination to hexahydroazepine (86 %).240... 

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