Eschweiler-Clark reaction

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-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). 

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 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). ... 

Formic acid Methylation of amines Clarke-Eschweiler reaction... 

The reductive alkylation reaction under Clarke-Eschweiler conditions has been shown to proceed through an iminium intermediate (142). 

Harding, J. R., Jones, J. R., Lu, S.-Y., Wood, R. Development of a microwave-enhanced isotopic labeling procedure based on the Eschweiler-Clarke methylation reaction. Tetrahedron Lett. 2002, 43, 9487-9488. 

For Petasis borono-Mannich reactions of formaldehyde, methylation of the amine reportedly occurs as a side-reaction, presumably by iminium ion reduction [19]. The hydride source under these conditions may be formic acid, as in the Eschweiler-Clarke methylation reaction. This problem was overcome by the use of potassium trifluoroborate salts and Lewis acids in toluene at 90 °C (the reaction in highly polar solvents such as acetonitrile, DMF and DM SO gives the reduction product). 

Grieco s synthesis of cryptopleurine 70 and julandine 68 (see end of section 2.3.1), via an intramolecular imino Diels-Alder reaction for construction of the quinolizidine nucleus, failed in the case of the related indolizidine alkaloid, tylophorine [38]. Submitting phenanthryl amine 113 to the identical aza Diels-Alder conditions used for cryptopleurine only yields by-products (114), as a result of a Clarke-Eschweiler type of cyclization. No tylophorine is detected under these conditions ... 

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. 

Many of the modifications of the pyrazolone antiinflammatory agents are intended to increase the limited hydrophilicity of the parent molecules. Reaction of aminopyrine (157) with formaldehyde and sodium hydrogen sulfite affords dipyrone (158). The first step can be rationalized as an Eschweiler-Clark type N-methylation reaction, with bisulfite acting as the reducing agent. The resulting mono N-methyl analogue of 157 then apparently forms the sulfite adduct of the carbinolamine of formaldehyde. 

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 ... 

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