Leuckart reductive amination

Tab. 3.8 Microwave-mediated Leuckart reductive amination of carbonyl compounds in 30 min.

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. 

Loupy et al. (1996) reported the Leuckart reductive amination of carbonyl compounds with ammonium formate or formamide. The reaction was carried out under solvent-free condition with microwave irradiation (60 W). Excellent yields of N-alkylated formamides (75-97%) were produced in reaction time of about 30 min. 

Microwave-mediated Leuckart reductive amination of carbonyl compounds was carried out (Loupy et al, 1996). They observed a strong specific (nonthermal) activation effect of microwaves. The yields obtained were excellent (75-97%) within short reaction time compared to conventional harsh conditions. 

LEUCKART - WALLACH ReductiveAmination Reductive amination of cartx)nyi groups with amines arxl formic add or Hj-NI (Miquonac) or NaBH4 (see Botch). 

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-... 

Scheme 34 Leuckart-Wallach reductive amination of aminobornanones...

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. 

The Wallach-Leuckart reductive alkylation of ammonia, and primary and secondary amines, by means of aldehydes and ketones, and the methylation of secondary amines according to Clarke and Eschweiler,3160 all possess a reduction step which is very similar to that observed in the reduction of enamines.317... 

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. 

The reductive amination of ketones by the Leuckart method utilizes aimnonium formate both as the source of the nitrogen to form an imine while the formate acts as the reductant (Scheme 2.30b). 

Conditions normally suitable for Leuckart-Wallach reductive amination (90 % formic acid and A-methylformamide at 170 °C) converted 4-azacholest-5-en-3-one (144) into the 5a-saturated lactam (145). A 17-oxo-group was simultaneously converted into the 17j8-A-methylformamido-derivative. 

Various accounts report the synthesis of heterocyclic androstane derivatives. 17)8-Acetoxy-4-oxa-androst-2-ene (215) has been prepared in three steps from the hemiacetal (214). Since various 4-aza-steroids exhibit antimicrobial activity, several new 4-aza-androstanes have been prepared. The reduction of ring a enamine lactams, such as 4-aza-androst-5-ene-3,17-dione (216a), under conditions of the Leuckart-Wallace reductive amination, provided 17/ -(iV-methyl-... 

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 ". ... 

A-Formylamines can be prepared by the Leuckart reaction, a reductive amination of carbonyl compounds by reaction with formamide and formic acid. Evidence for an unprecedented intramolecular transamidation in the mechanism of enantioselective Leuckart reaction of 2-norbornanone with a (l-norbornyl)acetamide is presented. ... 

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. 

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,. 

---