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 carbonyl compound 1 is assumed to react first with amine 2 to give the unstable a-aminoalcohol 5 as intermediate, from which an iminium species 6 is 

Named Organic Reactions, Second Edition T. Laue and A. Plagens 2005 John Wiley Sons, Ltd ISBNs 0-470-01040-1 (HB) 0-470-01041-X (PB) 

A primary or secondary amine can be used, as well as ammonia. With respect to the carbonyl component used, the best results have been obtained with aromatic aldehydes and with high boiling ketones. 

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. 

Iodoform, a yellow precipitate in water, is often used for detection of methyl ketones. 

Amine synthesis from reductive amination of a ketone and an amine in the presence of excess formic acid, which serves as the reducing reagent by delivering a hydride. When the ketone is replaced by formaldehyde, it becomes Eschweiler-Clarke reductive alkylation of amines. 

Leuckart, R. Ber. Dtsch. Chem. Ges. 1885, 18, 2341. Carl L. R. A. Leuckart (1854—1889) was bom in Giessen, Germany. After studying under Bunsen, Kolbe, and von Baeyer, he became an assistant professor at Gottingen. Unfortunately, chemistry lost a brilliant contributor by his sudden death at age 35 as a result of a fall in his parent s house. 

WaUach, O. Justus Liebigs Ann. Chem. 1892, 272, 99. Otto Wallach (1847—1931), bom in Konigsberg, Prussia, studied under Wohler and Hofmann. He was the director of the Chemical Institute at Gottingen from 1889 to 1915. His book Terpene und Kampfer served as the foundation for future work in terpene chemistry. Wallach was awarded the Nobel Prize in Chemistry in 1910 for his work on alicyclic compounds. Moore, M. L. Org. React. 1948, 5, 301. (Review). 

Treatment of O-acylated hydroxamic acids with base provides isocyanates. 

Lessen, W. Ann. 1872, 161, 347. Wilhelm C. Lessen (1838—1906) was bom in Kreuznach, Germany. After his Ph.D. studies at Gottingen in 1862, he embarked on his independent academic career, and his interests centered on hydroxyamines. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 146, Springer-Verlag Berlin Heidelberg 2009 

An unexpected intramolecular transamidation via a Wagner-Meerwein shift after the Leuckart-Wallach reaction 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 156, Springer International Publishing Switzerland 2014 

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Applications in agrochemicals [42, 43], pharmaceuticals [44,45], and positron emission tomography (PET) [46, 47, 48 49] have resulted in the resuscitation of the Wallach reaction The Wallach technique provides high-specific-activity F-radiolabeled aromatic fluoride for PET studies, in contrast to the low-specific-ac-tivity product by the Balz-Schiemann route... 

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. 

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 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 Balz-Schiemann and Wallach reactions The Balz-Schiemann reaction (the thermal decomposition of an aryl diazonium salt. Scheme 46) was for many years the only practical method for the introduction of a fluorine atom into an aromatic ring not bearing electron-withdrawing substituents. This reaction, first reported in the late 1800s, was studied in fluorine-18 chemistry as early as 1967 [214]. It involves the generation of an aryl cation by thermal decomposition, which then reacts with solvent, nucleophiles or other species present to produce a substituted aromatic compound. Use of fluorine-18-labelled... 

The Wallach reaction, the thermal decomposition of an aryl triazene (Scheme 46), has also been attempted as an alternative to the Balz-Schiemann reaction [54,220,221]. Although a wide variety of experimental conditions have been tried, the radiochemical yields remain low. 

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... 

See also the Wallach Reaction and the Leuckart(-WaUach) Reaction. 

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 ... 

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