And the Wallach reaction

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... 

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. 

Some reactions that belong in this category have been considered in earlier chapters. Among these are the Tollens condensation (16-46), the benzil-benzilic acid rearrangement (18-6), and the Wallach rearrangement (18-43). 

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

Heterocyclic Amines. Heterocyclic amines can be alkylated with alkyl halides or with alcohols in the presence of hydrogen plus a nickel catalyst. The Wallach reaction for the alkylation of amines by the action of aldehydes or ketones and formic acid has been studied for piperidine. Reactions between toluene and cyclohexanone with piperidine and formic acid yielded 1-benzyl- and 1-cyclohexylpiperidine, respectively. An optimum amount of formic acid is desired since large amounts are harmful and wasteful. 

Over-halogenation is a common theme in functionalization of unsubstituted imidazoles and often leads chemists to install functionality early if possible. The Wallach synthesis of imidazoles allows for the installation of a chlorine atom at the 5 position. Such chemistry provides an intermediate that is useful in the synthesis of the immunosuppressant, azathioprine. The Wallach reaction is the treatment of oxalylamides with PCI5 or POCI3 to yield the corresponding iV-methyl-5-chloroimidazole. Nitration is selective at the 4-position to provide the imidazole properly functionalized to provide azathioprine. ... 

A variety of media have been used for the Wallach fluorination reaction anhydrous hydrogen fluoride alone or with cosolvents such as methylene chloride, benzene, or tetrahydrofuran and hydrogen fluoride-pyridine alone or with co solvents such as benzene, glyme, or acetic acid [42,43, 46 50] Solutions of cesium fluoride, tetraethylammonium fluoride, or tetrabutylammonium fluoride in strong acids such as methanesulfonic acid or trifiuoroacetic acid with numerous cosolvents have also been studied [48, 49]... 

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. 

It h-ds been prepared artificially by Wallach as a bye-product in the reduction of nitrosopinene, C Hj NOH. It is best prepared as follows Five grams of nitrosopinene are dissolved in 40 c.c. of warm glacial acetic acid, and sufiScient water added to produce a slight cloudiness. A large amount of zinc-dust is then added. After the reaction has become gradual, the mixture is heated on a water-bath under a reflux condenser for four hours, i he liquid is then filtered, and the filtrate steam distilled. Ihe distillate is exhausted with ether, the ether evaporated... 

A rearrangement reaction which has been much studied, and in many ways resembles the reaction of phenylhydroxylamines, is the Wallach rearrangement111 of azoxybenzene (LXVI) to give para hydroxyazobenzene (LXVII), viz. 

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]. 

In some way formally similar to the benzidine rearrangement is the Wallach rearrangement of azoxybenzene 23 to give 4-hydroxyazobenzene 24 in concentrated (typically 95%) H2SO4. The 2-hydroxy isomer is sometimes formed in low yield with some substituted azoxybenzenes, and it is the main product in the photochemically induced reaction. Much of what is known about the reaction has been covered in earlier review articles28-30. This contribution will report work published since 1981. 

The Wallach rearrangement has been reported for perfluoro derivatives36. Reactions are much slower, as expected, and in sulphuric acid the octafluoro compound 35 gave no rearrangement product, but in chlorosulphuric acid rearrangement did occur to give the 4-chlorosulphonate ester. 

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 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... 

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