Eschweiler-Clarke Reaction

08 Feb

Eschweiler-Clarke Reaction

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.

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

Lab Tips

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]

_{1. Kürti, L., Czakó, B. (2005). Strategic Applications of Named Reactions in Organic Synthesis; Background and Detailed Mechanisms. Burlington, MA: Elsevier Academic Press.
2. Moore, M. L. Leuckart reaction. Org. React. 1949, 5, 301-330.
3. Cope, A.C., Burrows, W. D. Clarke-Eschweiler cyclization. Scope and mechanism. J. Org. Chem. 1966, 31, 3099-3103.}