Methylation of amines

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

The reaction of diazo compounds with amines is similar to 10-15. The acidity of amines is not great enough for the reaction to proceed without a catalyst, but BF3, which converts the amine to the F3B-NHR2 complex, enables the reaction to take place. Cuprous cyanide can also be used as a catalyst. The most common substrate is diazomethane, in which case this is a method for the methylation of amines. Ammonia has been used as the amine but, as in the case of 10-44, mixtures of primary, secondary, and tertiary amines are obtained. Primary aliphatic amines give mixtures of secondary and tertiary amines. Secondary amines give successful alkylation. Primary aromatic amines also give the reaction, but diaryl or arylalkyl-amines react very poorly. 

Methyl transferases are responsible for methylation of a nucleophile, typically using SAM as the carbon donor. They are known to accept a wide range of nucleophiles such as halides (eq. 1 in Figure 13.22) [64], amines (eq. 2 in Figure 13.22) [65], hydroxyls, and enolates. As expected, the reactivity of methyl transfer to halides follows the order of iodide, bromide, and chloride, with chloride being the poorest acceptor. Methylation of amines in nucleotides and proteins plays important roles in biological activities. 

Scheme 2 shows Rapoport s synthesis [15]. The cinnamic acid derivative 3 prepared from m-methoxy benzaldehyde [20] was ethylated by diethyl sulfate to give ethyl cinnamate derivative 4, followed by Michael addition with ethyl cyanoacetate to afford compound 5. Compound 5 was converted to lactam 6 by the reduction of the cyano group and subsequent cyclization. Selective reduction of the lactam moiety of 6 was achieved by treatment with trimethy-loxonium fluorob orate followed by sodium borohydride reduction. Amine 8 was obtained by the reductive methylation of amine 7. Amine 8 was converted to compound 9 by methylene lactam rearrangement [21], followed by selenium dioxide oxidation to provide compound 10. Allylic rearrangement of compound 10 and subsequent hydrolysis gave compound 12. The construction of the decahydroisoquinoline structure began with compound 12,... 

The reduction of enamine unit occurs much more rapidly than that of the carbonyl group. Therefore, this reagent can be used to perform reductive amination of aldehydes and ketones, by simply reacting the carbonyl compound with a fourfold excess of the amine. In a similar manner, reductive methylation of amines could be accomplished by addition of formaldehyde to the amine119. 

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 ... 

Methylation of amines. An aliphatic or aromatic amine ranging in basicity from pK 10.66 to 2.47 can be reductivciy methylated by aqueous formaldehyde and NaBHjCN in acetonitrile. Yields range from 45 to 90%. The procedure is superior to the Clarke-Eschweiler method, which can lead to complex mixtures. ... 

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. 

The formation of quaternary ammonium salts, followed by an elimination of the kind just described, is very useful in the determination of the structures of certain complicated nitrogen-containing compounds. The compound, which may be a primary, secondary, or tertiary amine, is converted into the quaternary ammonium hydroxide by treatment with excess methyl iodide and silver oxide. The number of methyl groups taken up by nitrogen depends upon the class of the amine a primary amine will take up three methyl groups, a secondary amine will take up two, and a tertiary amine only one. This process is known as exhaustive methylation of amines. 

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. 

The methylation of amines by formic acid and formaldehyde 23 is evidently a special case of the Leuckart reaction. 

The application in the N-methylation of alkaloids has been published [SH3]. The N-methylation of amines by paraformaldehyde-NaBH4 in CF3COOH in the presence or absence of THF or by CH20-NaCNBH3 in AcOH has also been recommended [GN3]. However, this method is limited because it is not possible to make monomethylated amines from primary amines the transformation of the intermediate secondary amine to tertiary amine is very rapid [AC5]. The best way to prepare monomethylated amines is then via the carbamates (Section 3.2.8). 

Moreover, the catalysts promoted by alkaline or alkaline-earth species are more stable than the unpromoted CuCr. For example, barium impregnated on copper chromite increases the stability of the active CuCr02 phase (13). Furthermore, the presence of barium or calcium on copper chromite catalysts influences strongly the selectivity to the methylation of amines N-alkylation/N-methylation. 

Methylation of amines in nucleotides and proteins plays important roles in biological function. Methyl transferases accept a wide range of nucleophiles such as halides, amines, hydroxyls, and enolates [reactions (a) and (b), Scheme 8.6] [42-44], For example, in the biosynthesis of novobiocin, methylation takes place at only one phenolic carbon and not the remaining three hydroxyl groups [45, 46]. On the other hand, methyl transfer to electron-deficient substrates often occurs under radical mechanisms requiring methylcobalamin as the cofactor, as shown in the biosynthesis of fosfomycin, where only one of the two enantiotopic hydrogen was replaced by the methyl group [reaction (c), Scheme 8.6] [47]. 

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. 

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. 

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