Reductive amination, Leuckart-Wallach reaction

By application of the Leuckart-Wallach reaction,amines 2 can be alkylated with a carbonyl compound 1 formic acid is used as reductive agent, and is in turn oxidized to give carbon dioxide. 

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 reductive alkylation of amines is called the Leuckart-Wallach reaction [112-115]. The primary or secondary amine reacts with the ketone or aldehyde. The formed imine is then reduced with formic acid as hydrogen donor (Scheme 20.27). When amines are reductively methylated with formaldehyde and formic acid, the process is termed the Eschweiler-Clarke procedure [116, 117]. 

The synthesis of amines by the in-situ reductive amination of ketones is termed the Leuckart-Wallach reaction. Recently, an asymmetric transfer hydrogenation version of this reaction has been realized [85]. Whilst many catalysts tested give significant amounts of the alcohol, a few produced almost quantitative levels of the chiral amine, in high enantiomeric excess. 

Reductive methylation of primary or secondary amines using formaldehyde and formic acid. Cf. Leuckart-Wallach reaction. 

Leuckart-Wallach reaction. Reductive alkylation of ammonia or of primary or secondary amines with carbonyl compounds and formic acid or formamides as reducing agents. 

The Eschweiler-Clarke reaction is the reductive methylation of amines 1, both primary and secondary, using formaldehyde (2) and formic acid (3).1 2 This represents a specific application of the Leuckart-Wallach reaction. 

The mechanism of the Leuckart-Wallach reaction has been the subject of much discussion and is generally accepted to proceed via the reaction of the amine with the carbonyl functionality to give an a-amino alcohol, which dehydrates to give an iminium ion.3 The reduction of this iminium is effected by formic acid.6-8... 

Recently, the application of microwave conditions to reactions that normally proceed thermally, but with long reaction times, has led to a much-hastened procedure for the Leuckart-Wallach reaction. 9 Loupy et al. have carried out the reductive amination of various aromatic ketones using a 1 3 3 ratio of carbonyl formamide formic acid under microwave irradiation for 30 minutes to produce the corresponding amines in high yields.19 In comparative studies the authors report considerable improvements in yield with microwave use. 

Another interesting enzyme class is amine dehydrr enases, which catalyze the oxidation of amines to ketones and ammonia or the inverse reductive reaction providing the enzymatic counterpart to the Leuckart-Wallach reaction (Scheme 2.8)... 

The previous sections have dealt with stable C=N-I- functionality in aromatic rings as simple salts. Another class of iminium salt reactions can be found where the iminium salt is only an intermediate. The purpose of this section is to point out these reactions even though they do not show any striking differences in their reactivity from stable iminium salts. Such intermediates arise from a-chloroamines (133-135), isomerization of oxazolidines (136), reduction of a-aminoketones by the Clemmensen method (137-139), reductive alkylation by the Leuckart-Wallach (140-141) or Clarke-Eschweiler reaction (142), mercuric acetate oxidation of amines (46,93), and in reactions such as ketene with enamines (143). 

Pr)4, " borohydride-exchange resin,and formic acid. When the last is used, the process is called the Wallach reaction. Conjugated aldehydes are converted to alkenyl-amines with the amine/silica gel followed by reduction with zinc borohydride.In the particular case where primary or secondary amines are reductively methylated with formaldehyde and formic acid, the method is called the Esch-weiler-Clarke procedure. It is possible to use ammonium (or amine) salts of formic acid, " or formamides, as a substitute for the Wallach conditions. This method is called the Leuckart reaction,and in this case the products obtained are often the N-formyl derivatives of the amines instead of the free amines. Primary and secondary amines can be iV-ethylated (e.g., ArNHR ArNREt) by treatment with NaBH4 in acetic acid. Aldehydes react with aniline in the presence of Mont-morillonite KIO clay and microwaves to give the amine. Formaldehyde with formic acid converts secondary amines to the N-methyl derivative with microwave irradiation. 

Formic acid is a common degradation product of sugars and also the oxidation product of formaldehyde. It is effective as a specific reagent for reductive amination of imminium ions to give secondary amines in the Maillard reaction. The reaction is known as a Wallach or Leuckart reaction (reactions of formates or formamide) R R N+=CH-R - - H-COOH R R N-CH -R + CO,. 

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