Simplified Version of the Eschweiler-Clarke Reaction

Klim O. Biriukov, Evgeniya Podyacheva, Ignatii Tarabrin, Oleg I. Afanasyev, Denis Chusov*

*A. N. Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences, Vavilova St. 28, bld. 1, INEOS, 119334 Moscow, Russia, Email: denis.chusovgmail.com

K. O. Biriukov, E. Podyacheva, I. Tarabrin, O. I. Afanasyev, D. Chusov, J. Org. Chem., 2024, 89, 3580-3584.

DOI: 10.1021/acs.joc.3c02476

Abstract

The reductive potential of formaldehyde is sufficient to provide methylation of secondary amines in the absence of acidic additives. Various acid-sensitive moieties remain intact under the developed conditions. The scalability of the elaborated approach was shown for several products.

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proposed mechanism

Details

The document discusses a simplified version of the Eschweiler−Clarke reaction, traditionally a three-component process involving formaldehyde, amine, and formic acid. The new approach demonstrates that formaldehyde alone can methylate secondary amines without acidic additives, preserving various acid-sensitive moieties. The study optimized reaction conditions, finding that acetonitrile as a solvent and higher temperatures significantly improved yields. The method was scalable, as shown by the synthesis of the antifungal agent butenafine. The protocol was versatile, effectively methylating a wide range of secondary amines, including those with bulky or chiral structures, and was compatible with acid-sensitive protective groups like THP, TBS, Boc, and MOM. However, primary amines primarily formed 1,3,5-dioxazine derivatives. The proposed mechanism involves formaldehyde acting both as a carbon source and a reducing agent, forming an iminium cation that is reduced via a six-membered transition state. This new method offers a practical and efficient alternative to the classical Eschweiler−Clarke reaction, particularly for substrates with acidophobic groups. The research was supported by the Russian Science Foundation and involved contributions from multiple authors affiliated with various Russian institutions.

General procedure

A 12 mL vial was charged with amine (0.137 mmol, 100 mol%), acetonitrile (250 μL) and formaldehyde solution (37%, 77.9 μL, 10.96 mmol, 800 mol%). The vial was sealed and placed into a preheated oil bath. After 4 hours, the reaction mixture was cooled down, diluted with 5 mL of CH₂Cl₂, and dried with anhydrous Na₂SO₄. Then solvents were evaporated under reduced pressure. The residue was analyzed with NMR.

Key Words

Eschweiler-Clarke Reaction, Formaldehyde, Amines

ID: J42-Y2024