Eschweiler-Clarke method

Stereospecificity was also shown in the reductive aminomethyla-tion182 of 3-aminopropanol derivatives by the Eschweiler-Clark method. Threo-3-methyl-5,6-diphenyl- (62) and erythro-3-methyl-... 

C-16 -protons of other Buxus alkaloids. Attempted A-methylation of 148 to 150 according to the Eschweiler-Clarke method resulted in the cleavage of the cyclopropane ring and in production of an amorphous mixture therefore the A-methylation had to be carried out with methyl iodide. On the other hand, the dihydroderivative (149) can be readily methylated by the Eschweiler-Clarke method. 

The Pschorr reaction was described in connection with the synthesis of the papaverine (3) derivatives (350, 351). The synthesis of petaline (5b) was accomplished (352, 353). Escholamine (4a) and takatonine (4c) were synthesized by a modified Pomeranz-Fritsch reaction (354). The phenolic oxidation of (f )-(-)-N-methylcoclaurine (7c) and (S)-(+)-reticuline (7f) with peroxidase proved to be a failure (355). The oxidation of reticuline with ferricyanide yielded isoboldine (24c) and pallidine (43b) and the byproducts vanillin and thalifoline (2c) (355). A new synthesis of 3-oxo-papaverine was developed (356), and the Eschweiler-Clark method for the synthesis of codamine (7r) was modified (357). Oxidation of reticuline (7f) by enzymatic systems from homogenized P. rhoeas in the presence of hydrogen peroxide gave ( )-/3-hydroxyreticuline (10) (358). 

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... 

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 ... 

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... 

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... 

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. 

Reductive amination with formaldehyde and sodium cyanoborohydride provides a convenient method for methylation of a secondary amine (or dimethylation of a primary amine). An alternative procedure uses formaldehyde together with formic acid (HCOOH) as the source of hydride in what is termed the Eschweiler-Clark reaction. Deprotonation of formic acid provides the formate anion, which delivers hydride to the iminium ion with concomitant formation of carbon dioxide. 

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). 

N,N-Dimethylcyclohexylmethylamine has been prepared by reduction of N,N-dimethylcyclohexanecarboxamide with lithium aluminum hydride 2 3 by the action of dimethylformamide on cyclohexanecarboxaldehyde 4 by methylation of cyclohexyl-methylamine3 6 and of N-methylcyclohexylmethylamine by the Clarke-Eschweiler method (treatment with formaldehyde and formic acid) and by the action of dimethylamine on cyclo-hexylmethyl bromide.6... 

Preparative Methods methyl phenyl sulfoxide is treated with Hydrazoic Acid (generated by addition of sulfuric acid to a slurry of sodium azide) in chloroform maintained at 45 °C to produce -methyl- -phenylsulfoximine. The latter can be readily resolved using 10-Camphorsulfonic Acid, from the (+)-acid the salt of (+)-(5)-5 -methyl-5 -phenylsulfoximine is obtained pure by recrystallization. The Clarke-Eschweiler procedure using Formaldehyde and Formic Acid provides an effective method for conversion of the N-H sulfoximine to the title compound. ... 

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. ... 

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