Leuckart-Wallach reaction

The Leuckart-Wallach reaction992 consists of the reductive alkylation of ammonia or an amine by a carbonyl compound with formic acid or a derivative thereof as reducing agent  

Primary and secondary amines can be methylated in good yield to tertiary amines when formaldehyde is added about 1.0-1.25 moles of formaldehyde and 2-4 moles of formic acid are used for each methyl group to be introduced. 

Methylation of aliphatic amines to tertiary amines 1015 1 mole of a primary amine is added with cooling to a mixture of 5 moles of 90 % formic acid and 2.2 moles of 35 % formaldehyde solution. Secondary amines require only half of these amounts of formic acid and formaldehyde, but an excess is not disadvantageous. Reaction begins when the mixture is heated on a steam-bath. When the initial vigorous evolution of carbon dioxide ceases, the mixture must be heated for a further 2-4 h, in all for 8-12 h. Then somewhat more than 1 mole of hydrochloric acid is added and the formic acid and formaldehyde are distilled off. The colorless residue is dissolved in water and basified with 25 % sodium hydroxide solution, and the amine is distilled off in steam. The distillate is saturated with solid potassium hydroxide, and the oil that separates is dried over potassium hydroxide and distilled from sodium. The following tertiary amines were thus obtained in more than 80% yield iV,iV-dimethylbutyl-amine, b.p. 94° A TV-dimethylbenzylamine, b.p. 176-180° and 1-methylpiperidine, b.p. 106°. 

Methylated hydrazines cannot be obtained from hydrazine hydrate in this way.1016 

Because of the tendency of formaldehyde to react with the ring of aromatic amines, this procedure cannot be used satisfactorily with compounds such as 

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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. 

The synthesis of pyrrolizidine developed by LukeS and Sorm31 and by Micheel and Flitsch32 starts with furylacrylic acid (56) which is converted by the Markwald reaction into y-ketopimelic acid (57). The carbonyl group in 57 is replaced by an amino group via the oxime or by the Leuckart-Wallach reaction this substitution results immediately in the formation of the lactam 58, which can be converted by heat into 3,5-dioxopyrrolizidine (59). The latter compound yields pyrrolizidine... 

When heated with Raney nickel at 200°, substituted formamides rearrange with the elimination of ammonia to form a carbonyl compound (105). This is the reverse of the Leuckart-Wallach reaction. The reaction is postulated to take the following course ... 

Lukasiewiez, A. Mechanism of chemical reactions. I. Mechanism of the Leuckart-Wallach reaction and of the reduction of Schiff bases by... 

Interestingly, Wasserscheid et al. have developed an efficient method to prepare TSOS derived from alkaloids such as ephedrine or amino alcohols such as valinol. In both cases, TSOS were obtained on the kilogram scale using a three step procedure (Leuckart-Wallach reaction followed by alkylation with Me2S04 and anion metathesis) [25] (Fig. 8). 

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

Leuckart-Wallach reaction, 153 Levopimaric acid, 190, 342 Levulinic acid, 239... 

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... 

In 1931, Ingersoll et al. noted that formamide could act as an Intermediate, and consequently ammonium formate could be replaced with formamide in the Leuckart reaction,12 and in 1968, Bach carried out Leuckart-Wallach reactions on cyclic aliphatic ketones with dimethylformamide in high yields, and with reaction times of only 8-16 h.13... 

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. 

Martinez et al. have carried out several studies into the Leuckart-Wallach reaction on l-substituted-2-norbomanones.15,16 The expected products result from 2-norbonanone and (li )-Ar-(3,3-dimethyl-2-oxo-l-norbornyl)acetamine, but the reaction of (lR)-N-(7,7-dimethyl-2-oxo-l-norbornyl)acetamine gives rise to an unexpected intramolecular transamidation via a Wagner-Meerwein shift.15... 

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... 

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