Leuckart-Wallach reaction amines

H. Reaction with Formic and Trichloroacetic Acids Enamines derived from aldehydes have been treated with formic acid under the conditions of the Leuckart-Wallach reaction 141) to give saturated tertiary amines 142). The enamine (98) reacts vigorously with formic acid at room temperature to give N-isobutyl morpholine (204). 

It has been shown (140) that enamines react as well, if not better, under the conditions of the Leuckart-Wallach reaction to give amines than do ketones in the presence of ammonia, primary amines, or secondary amines. This implies that in the Leuckart-Wallach reaction the pathway may be through the enamine and, of course, the iminium salt. The Leuckart-Wallach reaction has been reviewed (141). Examples of enamines reduced under the conditions of the Leuckart-Wallach reaction are listed in Table 12. 

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 usual procedure is to simply heat a mixture of the starting materials. A common side-reaction is the polyalkylation it can be suppressed by employing an excess of amine. In addition carbonyl substrates with a-hydrogens may undergo competitive aldol reactions the corresponding reaction products may then undergo a subsequent Leuckart-Wallach reaction. 

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. 

In 1885, R. Leuckart reported that the reaction of ammonia and primary or secondary amines with ketones (and aldehydes) was possible with ammonium formate, to produce the corresponding primary, secondary, or tertiary amine.1 This reaction became known as the Leuckart reaction. In 1891, Wallach reported that the use of excess formic acid led to an improvement in yield, and that the reaction could be carried out at lower temperatures.2 The Leuckart-Wallach reaction was bom. Wallach went on to apply this reaction to a wide variety of carbonyl compounds, including alicyclic and terpenoid ketones.5... 

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... 

Kitamua et al. have identified a useful catalyst for the Leuckart-Wallach reaction that can be used to form primary amines at lower temperatures, and in a higher yield than the standard conditions.14 The reaction uses 0.5 mol% [RhCp Cl2]2 and a 1 5 substrate ammonium formate ratio. 

The Leuckart-Wallach reaction was originally used in wide scope for the reaction of aliphatic and alicyclic ketones with ammonia and primary and secondary amines.1-5 In... 

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. 

Among monoamines, both enantiomers of 1-phenylethylamine and their derivatives play a prominent role. They are commercially available, but can also be prepared by resolution of the racemate, obtainable by Leuckart- Wallach reaction of acetophenone1, with malic acid2 or, more conveniently, with tartaric acid in methanol3. They are used as chiral additives for the addition of zinc alkyls to aldehydes in Section D. 1.3.1.4., as copper complexes for the synthesis of biaryls in Section B.2., as lithium salts for enantioselective deprotonation in Section C., and as imines in Sections D.1.1.1.3.1., D.1.1.1,4.. D.1.4.4., D.1.5.2., D.1.5.8., D. 1.6.1.2.1., D.2.3.I., and D.8. A general procedure for the synthesis of imines from carbonyl compounds and primary amines, with many examples of both chiral carbonyl compounds and chiral amines is given in reference 4. 

Both enantiomers of the tertiary amine A. /V-dimcthyl-l-phenylethylamine are readily available by conventional Leuckart-Wallach reaction (formaldehyde/formic acid) of the enantiomers of 1-phenylethylamine l2-l3. The reaction is most conveniently performed by the technique developed for the racemate14. Both enantiomers are also commercially available and have been used for enantioselective deprotonations (Section C.) and as catalysts for the addition of dialkylzinc to aldehydes (Section D.1.3.1.4.). 

Optically active amines can also be generated directly from ketones with ammonium formate in a catalytic version of the Leuckart-Wallach reaction (Equation 15.89). The imine is derived from the ammonia generated from the ammonium formate, and the reducing equivalent is derived from the formate. In the presence of the [Ru(BINAP)Cl2]2 catalyst, the amine and formamide were formed as the major products. After hydrolysis of the formamide, the amine was isolated in high yield and ee. 

Studies have reported that the Leuckart-Wallach reaction is effective for the synthesis of chiral amines, with some very important contributions by Kadyrov and Riermeier, who employed a Ru(II)/BINAP derivative to excellent effect, yielding... 

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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