Clarke-Eschweiler reductive

A useful application is the Clark-Eschweiler reductive alkylation of amines. Heating a primary or secondary amine with formaldehyde and formic acid results in complete methylation to the tertiary amine. The hydride acceptor is the iminium ion resulting from condensation of the amine with formaldehyde. 

The previous sections have dealt with stable C=N-I- functionality in aromatic rings as simple salts. Another class of iminium salt reactions can be found where the iminium salt is only an intermediate. The purpose of this section is to point out these reactions even though they do not show any striking differences in their reactivity from stable iminium salts. Such intermediates arise from a-chloroamines (133-135), isomerization of oxazolidines (136), reduction of a-aminoketones by the Clemmensen method (137-139), reductive alkylation by the Leuckart-Wallach (140-141) or Clarke-Eschweiler reaction (142), mercuric acetate oxidation of amines (46,93), and in reactions such as ketene with enamines (143). 

The reductive alkylation reaction under Clarke-Eschweiler conditions has been shown to proceed through an iminium intermediate (142). 

N,N-Dimethylcyclohexylmethylamine has been prepared by reduction of N,N-dimethylcyclohexanecarboxamide with lithium aluminum hydride 2 3 by the action of dimethylformamide on cyclohexanecarboxaldehyde 4 by methylation of cyclohexyl-methylamine3 6 and of N-methylcyclohexylmethylamine by the Clarke-Eschweiler method (treatment with formaldehyde and formic acid) and by the action of dimethylamine on cyclo-hexylmethyl bromide.6... 

N-Methylation of secondary amines is usually accomplished either with CH20/HC02H (Leuckart/Clarke-Eschweiler reaction) or with CH20 followed by NaBH4 reduction. Methyl iodide treatment of secondary or tertiary bisben-zylisoquinoline alkaloids leads ultimately to the bis quaternary salts, and, in the presence of base, phenolic alkaloids are also O-alkylated. For example, lin-doldhamine (165) on treatment with ethyl bromide in 0.5 N ethanolic KOH gave the N,N,0,0,0-pentaethy 1 derivative (108, Section II,C,56) daurisoline was similarly permethylated with Mel and base (68, Section II,C,19). 

The usefulness of reductive amination is augmented by the facile methylation of amines with formaldehyde (usually in MeCN), which provides a convenient, mild alternative to Clark-Eschweiler and other methylation procedures. Table 8 presents a selection of successful methylation applications with various amines, and further illustrates the chemoselectivity and versatility of the process. 

M ethylation of amines,8 An aliphatic or aromatic amine ranging in basicity from pK. 10.66 to 2.47 can be reductively methylated by aqueous formaldehyde and NaBH3CN in acetonitrile. Yields range from 45 to 90%. The procedure is superior to the Clarke-Eschweiler method,9 which can lead to complex mixtures.10 R. C. Wade, E. A. Sullivan, J. R. Berschied, Jr and K. F. Purcell, Inorg. Chem., 9, 2146 (1970). 

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

ESCHWEILER CLARKE Aminemethylation Reductive methylation of amines by a mixture ot formaldehyde and formic acid... 

This reaction was initially reported by Eschweiler in 1905, and subsequently by Clarke and co-workers in 1933. It is the preparation of tertiary methylamines from primary or secondary amines by means of the treatment of those amines with an excess amount of aqueous formaldehyde and formic acid. Therefore, it is generally known as the Eschweiler-Clarke methylation. In addition, this reaction is also referred to as the Eschweiler-Clarke condition," Eschweiler-Clarke A -methylation, Eschweiler-Clarke procedure, -) Eschweiler-Clarke reaction, s.3j,7 Eschweiler-Clarke reductive methylation, Eschweiler-Clarke reductive -methylation, Clarke-Eschweiler methylation, Clarke-Eschweiler reaction,or Clarke-Eschweiler procedure. In this reaction, the formate anion donates its proton to reduce the imine or iminium salt, so that carbon dioxide is evolved. Thus the whole process is a reductive amination of formaldehyde. This reaction is very useful for the reductive amination, without the application of hydrogen gas, catalyst (e.g., Pd/C), and high-pressure apparatus and has been widely applied to alkaloid chemistry. A special case of such reductive amination that occurs on phenylethylamine and results in the formation of tetrahydroisoquinolines is also referred to as the Clarke-Eschweiler cyclization. In a few cases, the methylation also occurs on an aromatic ring during the reductive amination. J... 

The related Clarke-Eschweiler reaction in whidi the reductive alkylation of an amine is carried out with formaldehyde and formic acid was used to prepare 3-dimethylamino-l-phenyl-1-(2-pyridyl)ptopane (IX-2S8) from 3-phenyl-3-(2-pyridyl)propylamine (IX-257). ... 

An attractive feature of this route is that the macrobicyclic intermediate 40a can be readily N-alkylated without affecting the masked thiolate functions (209). Thus, reductive methylation of 40a with formaldehyde and formic acid under Eschweiler-Clarke conditions, followed by deprotection of 40b with Na/NH3 provides the otherwise inaccessible N6S2 ligand H2L19 in nearly quantitative yield (Scheme 1). Several other aza-thioethers 40c-p and their corresponding thiophenolate ligands were prepared by this route (see Fig. 30 and Table I) and some of them will be discussed further in later sections (210-215). 

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]. 

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 ... 

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. 

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