Eschweiler-Clarke methylation

What is Eschweiler-Clarke methylation?

The Eschweiler-Clarke methylation is a chemical reaction that was first reported by Eschweiler in 1905 and later by Clarke and co-workers in 1933. This method involves the conversion of primary or secondary amines to tertiary methylamines using an excess of aqueous formaldehyde and formic acid. Due to its originators, it is commonly known as the Eschweiler-Clarke methylation, but it is also referred to by several other names such as the Eschweiler-Clarke condition, Eschweiler-Clarke procedure, Eschweiler-Clarke reaction, or Eschweiler-Clarke reductive methylation. Additionally, it is sometimes called the Clarke-Eschweiler methylation, reaction, or procedure.

Eschweiler-Clarke methylation - general reaction scheme - Eschweiler-Clarke condition, procedure, reaction, or reductive - Clarke-Eschweiler methylation methylation
Eschweiler-Clarke methylation
  • R1 = H, alkyl, aryl
  • R2 = alkyl, aryl

During the reaction, the formate anion provides a proton to reduce the imine or iminium salt, causing carbon dioxide to be produced. Consequently, the entire process is a reductive amination of formaldehyde. This method is particularly useful because it doesn’t require hydrogen gas, a catalyst (e.g., Pd/C), or high-pressure equipment, making it widely applicable in alkaloid chemistry.

The Clarke-Eschweiler cyclization is a specific type of reductive amination that occurs on phenylethylamine, resulting in the formation of tetrahydroisoquinolines. In some instances, methylation can also occur on an aromatic ring during the reductive amination.