Eschweiler reaction

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 Eschweiler reaction (formaldehyde and formic acid) has been used for the pyr-A-methylation of l-methyl-l,2,3,4-tetrahydro-j8-carboline, as has formaldehyde and hydrogen in the presence of Raney nickel. Tetrahydroharmine has been reported to react with benzaldehyde to yield a condensation product, C33H36N403, which is presumably a pyr-iV-substituted derivative (318). It is not known whether a similar condensation product of benzaldehyde with harm-aline is a C- or V-substituted derivative of harmaline. Conden-... 

Reductive methylation is achieved by the reaction of formaldehyde with ammonium chloride. It is carried out by heating the components at 100-120° and gives mono-, di- and trimethylamine in high yields (Eschweiler reaction) [312, 962]. No catalyst is needed part of the formaldehyde provides the necessary hydrogen while the other part is oxidized to formic acid. The same reaction can be applied to methylation of primary and secondary amines [962]. Reductive alkylation can also be accomplished by reducing mixtures of amines with acids which are first reduced to aldehydes (p. 171). 

Curtius reaction of ester 196 in benzyl alcohol leads to benzylurethane 197, which by hydrolysis and catalytic reduction gives amine 198 (72JCS(P1)878, 69JCS(C)2235). The primary amino group of compound 198 was converted into dimethylamino using the Eschweiler reaction, and then selectively quaterniz. Hofmann cleavage of this salt then leads to furo[4,3,2-/g]benzazocine 199 (Scheme 54). 

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). 

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). ... 

Emde degradation of /S-carbohnes, 172 Epi position, definition of, 325 Equilibria, see tautomeric equilibria Eschweiler reaction, 87, 161 Eseroline, 106... 

Formic acid Methylation of amines Clarke-Eschweiler reaction... 

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