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Updated: Jun 28, 2025

Reliable Mechanochemistry: Protocols for Reproducible Outcomes of Neat and Liquid Assisted Ball-mill Grinding Experiments
Published on: January 23, 2018
Convenient and efficient N-methylation of secondary amines under solvent-free ball milling conditions
Mikołaj Walter1, Olga Ciupak1, Karol Biernacki1
1Department of Organic Chemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza 11/12, 80-233, Gdansk, Poland.
Abstract:
In the present work, we report the development of a rapid, efficient, and solvent-free procedure for the N-methylation of secondary amines under mechanochemical conditions. After optimization of the milling parameters, a vibrational ball mill was used to synthesize 26 tertiary N-methylated amine derivatives in a short time of 20 min (30 Hz frequency) and high yields ranging from 78 to 95%. An exception was compounds having a hydroxyl group in their structure, for which a decrease in reaction efficiency was observed. During our research, we investigated alternate reaction selectivity occurring in compounds able to form ring closure products that are 3,4-dihydro-2H-1,3-benzoxazine derivatives instead of N-methylated products. The liquid-assisted grinding technique has been applied using formalin as a methylating agent and sodium triacetoxyborohydride as a reducing agent in a reductive amination reaction.
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