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]
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.
Mechanism
Top Citations
Original Paper
Related Reactions
- Delepine Reaction
- Gabriel Synthesis
- Staudinger Reaction
Related Compounds
- Formic Acid (CAS 64-18-6)
- Formaldehyde (CAS 50-00-0)
