Iminium salts, reaction with formic acid

This reaction allows the preparation of tertiary methylamines from secondary amines via treatment with formaldehyde in the presence of formic acid. The formate anion acts as hydride donor to reduce the imine or iminium salt, so that the overall process is a reductive amination. The formation of quaternary amines is not possible. 

Iminium salts (2) can commonly be prepared from the reaction of amines with aldehydes or ketones (1 Scheme 1). With formaldehyde as the carbonyl precursor, Eschweiler-Clark-type methylation reactions may occur when using reducing acids such as formic acid. Alternatively, other sp -type, nitrogen-free carbonyl derivatives (3), such as acetals and hemiacetals, can be used, where this is favorable. Highly electron-poor carbonyls, such as chloral (c/. Scheme 10), may show distinctly decreased reactivity in aqueous solution, due to the extended hydrate formation. 

There are, however, numerous organic precendents. The Cannizzaro reaction, in which two equivalents of a nonenolizable aldehyde such as bezaldehyde are reacted with hydroxide to form a primary alcohol and the salt of a carboxylic acid, is thought to involve hydride transfer to one aldehyde carbonyl from the carbonyl-addition product of the other aldehyde and hydroxide. The Leuckart reaction, formation of a tertiary amine from formic acid, a primary amine and either a ketone or an aldehyde, seems to procede via hydride transfer from formate to an iminium ion. And the Meervein-Ponndorf-Verley-Oppenauer reaction, the reversible transfer of hydrogen between ketones and secondary alcohols in the presence of excess aluminum isopropoxide, is almost certainly a hydride-transfer reaction. This latter process is of particular interest to us because it requires a metal, just as GI does. The aluminum acts as a Lewis acid, coordinating the carbonyl oxygen and... 

Reduction of an amide provides a route to amine derivatives since the oxygen atom is removed. Forma-mide derivatives are easily synthesized by reaction of amines with ethyl formate, for example, and subsequent reduction provides an effective method for monomethylation and dimethylation of amines. Reaction of 2-phenylethanamine with formaldehyde and formic acid gave iminium salt 33 as a reactive intermediate, which... 

This reaction can also be utilized when there are heteroatom substituents. Reaction of amide-diene 97 with paraformaldehyde and formic acid generated iminium salt 98. Cationic cyclization (formate is the nucleophilic trapping agent) generated the perhydroisoquinoline 99. A related cyclization procedure that involves... 

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... 

Another synthesis of substituted amines mixes formic acid with an amine and formaldehyde. If 3-aminohexane (15) is treated with formaldehyde in the presence of formic acid, the initial product is iminium salt, 16. In the presence of formic acid, the n-bond of the imine donates electrons to the acidic proton to give an AT-methylamine product, 3-(AT-methylamino)hexane, 17. This particular reaction is called the Eschweiler-Clarke reaction, after Wilhelm Eschweiler (Germany 1860-1936) and Hans Thacher Clarke (England 1887-1972). It is also possible to mix formaldehyde and an amine in the presence of hydrogen... 

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