Reduction reactions Eschweiler-Clark reductive alkylation

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). 

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 ... 

A modified protocol of the Eschweiler-Clarke reaction, a reductive transamination, was also used for an efficient N-alkylation of hexahydroazepine and benzylamine in the presence of formic acid and aldehydes or ketones53. 

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. 

Lemaire et al. report an extension of the Eschweiler-Clarke reaction to allow the TV-alkylation of amides.8 Although many other methods for this reaction do exist,9 " they tend to be inefficient on secondary and cyclic amides" or compounds with low N-H acidity.9 In addition, this modification of the Eschweiler-Clarke reaction allows A-alkylation with a secondary alkylating agent, a reaction that would normally be impossible due to the competing elimination process.9 In the reaction, reductive alkylation is effected with an... 

Brewer, A. R. E. Eschweiler-Clarke reductive alkylation of amine. In Name Reactions for Functional Group Transformations-, Li, J. J., Corey, E. J., eds. John Wiley Sons Hoboken, NJ, 2007, pp 86-111. (Review). 

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). ... 

The Clark-Eschweiler reductive alkylation of amines is a useful example of this reaction. Heating a primary or secondary amine with formaldehyde and formic acid results in complete methylation to the tertiary amine. 

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). 

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