Eschweiler-Clarke procedure

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]. 

Phenylphosphinic acid and dialkyl sulphoxides are alternatives for, respectively, the reducing agent (formic acid) and the alkylating agent (an aldehyde) used for the TV-alkylation of secondary aliphatic amines (the Eschweiler-Clarke procedure) (equation 55b)166. 

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... 

Fache, F., Jacquot, L., Lemaire, M. Extension of the Eschweiler-Clarke procedure to the N-alkylation of amides. Tetrahedron Lett. 1994, 35, 3313-3314. 

Bulman Page, P. C., Heaney, H., Rassias, G. A., Reignier, S., Sampler, E. P., Talib, S. The reductive cleavage of cyclic aminol ethers to N,N-dialkylamino-derivatives. Modifications to the Eschweiler-Clarke procedure. Synlett 2000, 104-106. 

With a primary amine such as n-octylamine, we observe at low conversion (8 %) high selectivity for the N-monoalkylated product whereas 90 % N,N-dimethylated amine are formed at high conversion (94 %). In reductive alkylation, it is even more difficult to obtain the monomethylated product selectively. For example, in the Eschweiler Clarke procedure [17], only the dimethylated amine is formed, even with an amine-to-formaldehyde ratio of 1. In the Hofmann-type reaction, a mixture of mono- and dimethylamine with the corresponding trimethylammonium salt is generally produced. 

In their studies toward the synthesis of antioxidants, Wijtmans et al. have carried out several methylations of 2-aminopyridines, both cyclic and acyclic, in quantitative yields using the Eschweiler-Clarke procedure.19... 

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. 

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... 

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