Leuckart reaction / reductive amination

The Leuckart reaction (reductive amination of carbonyl compounds with formamide and formic acid) of 2-norbornanone and (lR)-(V-(3,3-dimethyl-2-oxo-l-norbornyl) acetamide furnishes the expected A-(2-norbornyl)formamides. (l/()-AI-(7,7-Dimethyl-2-0X0-l-norbornyl)acetamide, on the other hand, gives a product resulting from a Wagner-Meerwein rearrangement of the usual cationic intermediate followed by an unprecedented transamination, which affords an A,A-diacylammonium ion. Hydrolysis gives (15 )-A-(3,3-dimethyl-2-oxo-l-norbornyl)acetamide, which then undergoes the normal Leuckart reaction. 

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. 

Acetophenone similarly gives an oxime, CHjCCgHjlCtNOH, of m.p. 59° owing to its lower m.p. and its greater solubility in most liquids, it is not as suitable as the phenylhydrazone for characterising the ketone. Its chief use is for the preparation of 1-phenyl-ethylamine, CHjCCgHslCHNHj, which can be readily obtained by the reduction of the oxime or by the Leuckart reaction (p. 223), and which can then be resolved by d-tartaric acid and /-malic acid into optically active forms. The optically active amine is frequently used in turn for the resolution of racemic acids. 

The Leuckart reaction uses formic acid as reducing agent. Reductive alkylation using formaldehyde, hydrogen, and catalyst, usually nickel, is used commercially to prepare methylated amines. These tertiary amines are used to prepare quaternary ammonium salts. 

Another interesting fact to be noted is that the bicyclic enamine (87) and its pyrrolidine analogue failed to undergo reduction with 98% formic acid, whereas the pyrrolidine enamine of 2-bicyclo[2.2.1]hepten-5-carboxalde-hyde (94), which exists largely in the transoid form (49), was readily reduced to (95). However, the saturated amine-substituted norbornane can be obtained directly from norbornanone under the more vigorous conditions of the Leuckart reaction (49a). 

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. 

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 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. 

Eschweiler-Clarke modification org chem A modification of the Leuckart reaction, involving reductive alkylation of ammonia or amines (except tertiary amines) by formaldehyde and formic acid. esh,vTl-3r klark. mad-o-fo ka-shon ... 

Reductive alkylation can also be accomplished by heating carbonyl compounds at 150-250° with 4-5 mol of ammonium formate, formamide, or formates or formamides prepared by heating primary on secondary amines with formic acid at 180-190° (Leuckart reaction) [322]. An excess of85-90% formic acid is frequently used. Formyl derivatives of primary or secondary amines are sometimes obtained as products and have to be hydrolyzed to the corres-... 

Loupy, A., Monteux, D., Petit, A., Aizpurua, J.M., Dominguez, E. and Palomo, C., Towards the rehabilitation of the Leuckart reductive amination reaction using microwave technology, Tetrahedron Lett., 1996,37,8177-8180. 

A major variation is the use of formic acid or one of its derivatives as the reductant (the Leuckart reaction). In the synthesis of 1-phenylethylamine (Expt 5.197), ammonium formate is heated with aceptophenone while the water formed in the reaction is carefully removed by fractional distillation to give the required amine as its N-formyl derivative, (l-phenylethyl)formamide. This is then hydrolysed with acid to yield the primary amine. The procedure has been satisfactorily applied to many aliphatic-aromatic, alicyclic and aliphatic-heterocyclic ketones, some aromatic ketones and aldehydes, and to some aliphatic aldehydes and ketones boiling at about 100 °C or higher. 

The first reported synthesis of MDMA was from safrole by converting it to its bromo derivative followed by reaction with meth-ylamine (Biniecki et al., 1960). Bailey et al. describe the synthesis of MDMA from 3,4-methylenedioxyphenylacetone using a Leuckart reaction with N-methylformamide and hydrolysis of the N-formyl derivative (Bailey et al., 1975). A third synthesis for MDMA described in the literature starts with peperonal which is reacted with nitroethane, ammonium acetate, and acetic acid to form a nitrostyrene derivative that is reduced to the ketone and then reacted with methylamine to form MDMA (Rabjohns, 1963). Using the method of Borch et al., MDMA can be synthesized by the reductive amination of the appropriate ketone in the presence of sodium cyanoborohydride (Borch et al., 1971). The MDMA syntheses used in clandestine laboratories are analogous. 

Alkyl groups may be introduced into ammonia, a primary amine, or a secondary amine by means of an aldehyde or ketone in the presence of a reducing agent, such as molecular hydrogen and a catalyst, active metals and acids, or formic acid or one of its derivatives. When the reducing agent is formic acid or a derivative, the reaction is known as the Leuckart reaction and is discussed elsewhere (method 432). An excellent review of the preparation of amines by reductive alkylation has been presented. This article includes a discussion of the scope and utility of the reaction, a selection of experimental conditions, illustrative preparations, and a tabulation of primary, secondary, and tertiary amines prepared thereby. ... 

Several methods are available for the preparation of tertiary amines from fatty acids. One of the oldest is the classical Leuckart reaction (32), which uses formaldehyde and formic acid for the reductive alkylation of a secondary amine. 

Eschweiler-Clarke reaction. Reductive methylation of primary or secondary amines with formaldehyde and formic acid (special form of the 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. 

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. 

Leuckart-like reactions have been noted for the co-phosphinoylalkanals 304 and related compounds In these reactions, and also for those with analogous ketones the carbonyl reactant is subjected to reductive amination with ammonia (as ammonium acetate) or amines and NaBH3CN in MeOH at pH 7-7.5 the process is very sensitive to steric hindrance and probably proceeds via an enaminophonate intermediate. The sequence is illustrated (Scheme 38) by a direct synthesis of racemic phosphinothricin, but the involvement of the optically active 1,2-azaphospholidine 118 led to an optically active product ". ... 

Methylation of Primary and Secondary Fatty Amines. This is done by the Leuckart reaction (1,30) or reductive methjiation... 

---