Amination by Reduction

Amines are divided into three classes—primary, secondary, and tertiary —depending upon the number of replaced hydrogens in the parent substance ammonia. Primary amines contain two remaining hydrogen atoms attached to the ammonia nitrogen, secondary amines contain one, and tertiary amines have none remaining. 

Amides, in contrast to amines, are derivatives of ammonia, where one of the hydrogens has been replaced by an organic acid-derived group, such as acyl, aroyl, heteroyl, sulfonyl, etc. An imide is one in which two hydrogens of the parent ammonia have been so replaced. 

Amides are generally prepared by ammonolysis reactions and not by reductive methods. 

The methods generally used for the preparation of primary amines are the following  

The reduction of nitro, nitroso, hydroxylamino, azojgr, azo, and hydrazo compounds. 

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Aldehydes and ketones may be converted into the corresponding primary amines by reduction of their oximes or hydrazones (p. 93). A method of more limited application, known as the Leuckart Reaction, consists of heating the carbonyl compound with ammonium formate, whereby the formyLamino derivative is formed, and can be readily hydrolysed by acids to the amine. Thus acetophenone gives the i-phenylethylformamide, which without isolation can be hydrolysed to i-phenylethylamine. 

AletalHydrides. Metal hydrides can sometimes be used to prepare amines by reduction of various functional groups, but they are seldom the preferred method. Most metal hydrides do not reduce nitro compounds at all (64), although aUphatic nitro compounds can be reduced to amines with lithium aluminum hydride. When aromatic amines are reduced with this reagent, a2o compounds are produced. Nitriles, on the other hand, can be reduced to amines with lithium aluminum hydride or sodium borohydride under certain conditions. Other functional groups which can be reduced to amines using metal hydrides include amides, oximes, isocyanates, isothiocyanates, and a2ides (64). 

Aminophenols are either made by reduction of nitrophenols or by substitution. Reduction is accompHshed with iron or hydrogen in the presence of a catalyst. Catalytic reduction is the method of choice for the production of 2- and 4-aminophenol (see Amines BY reduction). Electrolytic reduction is also under industrial consideration and substitution reactions provide the major source of 3-aminophenol. 

Irradiation of 3,5-disubstituted isoxazoles in alcoholic solvents gave reaction products such as acetals incorporating the reaction solvent. The use of triethylamine in acetonitrile media produced ketene-aminals by reductive ring cleavage. The reductive ring cleavage product was also obtained by irradiation of the isoxazole in alcohol in the presence of copper(II) salts (Scheme 3) (76JCS(P1)783). 

One of the syntheses of f1 udalanine begins with base promoted condensation of ethyl fluoroacetate and ethyl oxalate to give This is then converted by hydrolytic processes to the insoluble hydrated lithium salt of fluoropyruvate (58). This last is reductively aminated by reduction with sodium boro-deuteride and the resulting racemate is resolved to give D-flu-dalanine (59). 

R. L. Sandriikif u. H.B. Staley. Amines by reduction, Kirk-Othmer Encycl. Chem. Technol., 3. Aufl. 2, 355 (1978). 

For a review of the preparation of tertiary amines by reductive alkylation, see Spialter, L. ... 

Cholest-3-ene has been prepared previously by deamination of 5/3-cholestan-3 -yl amine,by reduction of a mixture of 4 -bromo-5 -cholestan-3a-ol and its epimer with zinc in acetic acid, and as component of a mixture of cholestenes by Wolff-Kishner reduction of cholest-4-en-3-one. ... 

The Leuckart-Wallach reaction is the oldest method of reductive amination of carbonyl compounds. It makes use of formamide, formic acid or ammonium formate at high temperature. The final product is a formamide derivative, which can be converted to an amine by reduction or hydrolysis. The method has been applied to the preparation of 1,2-diamines with a norbornane framework, which are interesting rigid analogues of 1,2-diaminocyclohexanes. As a matter of fact, starting from N-acetyl-2-oxo-l-norbornylamine 222, the diamide 223 was obtained with excellent diastereoselectivity and then converted to the M-methyl-N -ethyl derivative 224 by reduction with borane [ 104] (Scheme 34). On the other hand, when the reac-... 

The electrophilic character of sulfur dioxide does not only enable addition to reactive nucleophiles, but also to electrons forming sulfur dioxide radical anions which possess the requirements of a captodative" stabilization (equation 83). This electron transfer occurs electrochemically or chemically under Leuckart-Wallach conditions (formic acid/tertiary amine - , by reduction of sulfur dioxide with l-benzyl-1,4-dihydronicotinamide or with Rongalite The radical anion behaves as an efficient nucleophile and affords the generation of sulfones with alkyl halides " and Michael-acceptor olefins (equations 84 and 85). 

A valuable application of sodium cyanoborohydride is in the synthesis of amines by reductive amination. What combination of carbonyl and amine components would give the following amines by this method ... 

Nitro compounds are versatile precursors for diverse functionalities. Their conversion into carbonyl compounds by the Nef reaction and into amines by reduction are the most widely used processes in organic synthesis using nitro compounds. In addition, dehydration of primary nitro compounds leads to nitrile oxides, a class of reactive 1,3-dipolar reagents. Nitro compounds are also good precursors for various nitrogen derivatives such as nitriles, oximes, hydroxylamines, and imines. These transformations of nitro compounds are well established and are used routinely in organic synthesis. 

Aluminum ethoxide, 21, 9 Aluminum isopropoxide, 21, 9 Amalgamated zinc, 20, 57 23, 86 Amide, 20, 37, 62, 66 preparation by ammonolysis, 20, 62 Amination, by reduction of a ketone in the presence of ammonia, 23, 68 of bromoacetal with use of high-pressure hydrogenation bomb, 24, 3 of a-bromoisocaproic acid, 21, 75 of a -bromo-/3-methylvaleric acid, 21, 62... 

This procedure illustrates a general method for the preparation of amines by reductive cleavage of sulfonamides by hydrobromic acid in the presence of phenol.9 The present synthesis makes 1,3-dihydroisoindole readily accessible and is superior in certain respects to the other two practical methods of preparation. Thus the method here described is shorter and gives a higher overall yield than the three-step synthesis of Neumeyer,7 and obviates the special apparatus and careful control required by the electrochemical process of Dunet, Rollet, and Willemart.4... 

Addition of RMgBr to nitriles. Grignard reagents react with nitriles slowly if at all, but even r-butylmagnesium chloride will add to nitriles in refluxing THF when catalyzed by a copper(I) salt. The adduct can be converted to a ketimine by anhydrous protonation, to a primary amine by reduction (Li/NH,), or to a ketone by hydrolysis. The actual reagent may be a cuprate such as R3Cu(MgX)2. 

Amines. See also Amines by reduction Cycloaliphatic amines Fatty amines Higher aliphatic amines Lower aliphatic amines... 

Metal alkyl cocatalysts, 20 153 Metal-alkylidene catalysts, 26 948 Metal-alkylidene complexes, 26 927 discovery of, 26 925 Metal amalgams, amines by reduction, 2 492 93... 

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