Known also as the "Eschweiler-Clarke methylation", this reaction converts a 1° or 2° amine to a 3° amine in a one-pot reaction with excess aqueous formic acid and formaldehyde. An iminium ion is first formed from the starting amine and formaldehyde via an aminal intermediate. A hydride transfer from the reducing agent to the carbon of the imine, along with loss of CO₂, results in the corresponding N-methylated amine. This process occurs twice for primary amines.

• Other reducing agents can be used, including formic acid derivatives, sodium borohydride, sodium cyanoborohydride, borohydride exchange resin, hydrogen gas/catalyst, etc. ^[1]
• An N-alkylated amine can be obtained when a ketone or aldehyde starting material is used instead of formaldehyde (Leuckart-Wallach reaction). ^[2]
• When the amine substrate is unsaturated, it is possible to obtain a cyclic 2° or 3° amine product under similar reaction conditions. This process is referred to as the Eschweiler-Clarke cyclization. ^[3]

• Reagents: Reducing Agent (Ex. Formic Acid)
• Reactant: 1° or 2° Amine, Formaldehyde
• Product: 3° N-Methylated Amine
• Type of Reaction: Reductive Alkylation

Mechanism

Original Paper

Top Citations

Related Reactions

Related Compounds