ESCHWEILER • CLARKE Amine methylation

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

Iminium salts (2) can commonly be prepared from the reaction of amines with aldehydes or ketones (1 Scheme 1). With formaldehyde as the carbonyl precursor, Eschweiler-Clark-type methylation reactions may occur when using reducing acids such as formic acid. Alternatively, other sp -type, nitrogen-free carbonyl derivatives (3), such as acetals and hemiacetals, can be used, where this is favorable. Highly electron-poor carbonyls, such as chloral (c/. Scheme 10), may show distinctly decreased reactivity in aqueous solution, due to the extended hydrate formation. 

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 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]. 

For ammonia and primary amines there are two possible pathways, but when secondary amines are involved, only the hydrogenolysis pathway is possible. Other reducing agents167 can be used instead of hydrogen and a catalyst, among them zinc and HCI, sodium cyano-borohydride NaBHjCN,168 sodium triacetoxyborohydride,169 sodium borohydride,170 iron pentacarbonyl and alcoholic KOH,171 BH -pyridine,172 and formic acid. When the last is used, the process is called the Wallach reaction. In the particular case where primary or secondary amines are reductively methylated with formaldehyde and formic acid, the method is called the Eschweiler-Clarke procedure. It is possible to use ammonium (or amine) salts of formic acid,173 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 N-ethylated (e.g., ArNHR —< ArNREt) by treatment with NaBH4 in acetic acid.175... 

It is usually straightforward to poly-A-acylate or A-alkylate an aza crown. For example A-methylation of ring secondary amines is conveniently achieved using the Eschweiler-Clarke reaction involving condensation of the... 

The reductive methylation of amines with formaldehyde in the presence of formic acid. See Lindeke, B., Anderson, B., and Jenden, D.J., Specific deuteromethylation by the Eschweiler-Clark reaction. Synthesis of differently labelled variants of trimethylamine and their use of the preparation of labelled choline and acetylcholine, Biomed. Mass Spectrom. 3, 257-259, 1976 Boldavalli, E, Bruno, O., Mariani, E. et al.. Esters of A-methyl-iV-(2-hydroxyethyl or... 

Methylation of amines. The classical method for methylation of primary or secondary amines is the Eschweiler -Clarke reaction. The reaction involves treatment of an amine with formaldehyde and formic acid ... 

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. 

Both the primary amine funtuphyllamine-A (XXVI) and the secondary base funtuphyllamine-B (XXVII) gave funtuphyllamine-C (XXVIII) on Eschweiler-Clarke methylation. The structure of funtu-phyllamine-B follows from the result of the Ruschig degradation (conversion of a primary or secondary base to a ketone via chloramine and ketimine) (19), which furnished 3 -hydroxy-5 -pregnan-20-one. 0-Acetylfuntuphyllamine-C proved to be identical with the known (20) 3 -acetoxy-20a-dimethylamino-6a-pregnane. Funtuphyllamine-B is... 

The mechanism of all of the above mentioned reactions is essentially the same. However, some steps in the mechanism are still not fully understood. The following steps are believed to be involved in the Eschweiler-Clarke methylation 1) formation of a Schiff-base (imine) from the starting primary or secondary amine and formaldehyde via an aminoalcohol (aminal) intermediate 2) hydride transfer from the reducing agent (e.g., formic acid, cyanoborohydride, etc.) to the imine to get the corresponding A/-methylated amine along with the loss of CO2 and 3) if the starting amine was primary, then steps 1 and 2 are repeated. 

Eschweiler-Clarke methylation One-pot reductive methylation of primary and secondary amines to the corresponding tertiary amines using formaldehyde and a reducing agent. 160... 

Rosenau, T., Potthast, A., Rohrling, J., Hofinger, A., Sixta, H., Kosma, P. A solvent-free and formalin-free Eschweiler-Clarke methylation of amines. Synth. Common. 2002, 32, 457-465. 

Eschweiler-Clarke reaction The reductive methylation reaction of an amine with methanal and methanoic acid to give the A-methyl derivative. 

Iminium ion-alkene cyclizations accomplished under standard Eschweiler-Clarke methylation conditions have been employed to prepare five-, six- and seven-membered azacycles (Scheme 25).57,58 It is important to note that under identical conditions amines (62) and (63) did not cyclize but afforded the corresponding IVjV-dimethylamines. With regard to the alkene participant these results are in full accord with Baldwin s rules for ring formation.2 However, the formation of pyrrolidine (61) demonstrates that 5-endo-trig cyclizations2 can take place with respect to the iminium ion n-participant. The observed regioselectivity and the failure of (63) to cyclize are in accord with obligatory formation of an intermediate with tertiary carbocation character. 

The reactions of the completely reduced compounds have attracted much attention because of their close relationship to piperazine. Thus it has been shown, as might be expected, that the 2-position in compounds such as the parent 100 can be readily acetylated and benzoylated" and ureas are formed with phenylisocyanate and phenylisothiocyanate." Compound 100 also reacts at the 2-position with p-acetamidobenzene-sulfonyl chloride to give a sulfonamide. There are several examples of the alkylation of the amine in the 2-position. Various alkyl halides -have been used, as well as ethylene oxide," p-nitrobenzoyl-ethyleneimine, " and l-guanyl-3,5-dimethylpyrazole nitrate. Compound 100 also undergoes the Eschweiler-Clarke modification of the Leuckart reaction to give the 2-methyl compound." ... 

The Eschweiler-Clarke reaction is the reductive methylation of amines 1, both primary and secondary, using formaldehyde (2) and formic acid (3).1 2 This represents a specific application of the Leuckart-Wallach reaction. 

In contrast to other methods for the methylation of primary amines, for example, the use of methyl iodide, this method leads to good yields of the iV,iV-dimethyl tertiary amines, without the formation of quaternary salt products.3 In comparison to reductive animation techniques, the reagents for the Eschweiler-Clarke reaction are cheap, and the reaction is easily scaled up.4... 

The mechanism of the Eschweiler-Clarke reaction proceeds via the formation of an imine, followed by reduction by formic acid. That the methylation is attributable to the formaldehyde and the reduction to the formic acid has been confirmed using 14C-labeled isomers of each in a series of studies.5 Thus, the amine reacts with formaldehyde to produce an imine, and this is then reduced with the loss of carbon dioxide by formic acid. In the case of primary amines this process is then repeated to produce a tertiary N.iV-dimethyl amine. 

The Eschweiler-Clarke reaction represents a synthetically useful method for the methylation of amines that avoids quatemisation and is easy to scale up. The reaction conserves stereocentres present elsewhere, and has been shown to be possible with less toxic reagents, in solvent-free conditions. 

Another classical alternative is the Eschweiler-Clarke procedure, that involves drastic experimental conditions in which a solution of 88% aqueous formic acid, 35% aqueous formaldehyde and the corresponding primary amine in dimethylformamide is refluxed for 5 hr.10 Moreover, only methylated amines can be prepared. 

We realized that using a low boiling liquid in a microwave environment, even on a small scale, did not constitute best practice and as for hydrogenations our thoughts turned to using formates in a modified Eschweiler-Clarke reaction [79-81] and successfully methylated a number of primary and secondary amines under microwave conditions (Scheme 18.9) [82]. 

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