Convenient and efficient N-methylation of secondary amines under solvent-free ball milling conditions

Mikołaj Walter; Olga Ciupak; Karol Biernacki; Janusz Rachoń; Dariusz Witt; Sebastian Demkowicz

doi:10.1038/s41598-024-59374-z

Convenient and efficient N-methylation of secondary amines under solvent-free ball milling conditions

Sci Rep. 2024 Apr 16;14(1):8810. doi: 10.1038/s41598-024-59374-z.

Authors

Mikołaj Walter¹, Olga Ciupak¹, Karol Biernacki¹, Janusz Rachoń¹, Dariusz Witt¹, Sebastian Demkowicz²

Affiliations

¹ Department of Organic Chemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza 11/12, 80-233, Gdansk, Poland.
² Department of Organic Chemistry, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza 11/12, 80-233, Gdansk, Poland. sebdemko@pg.gda.pl.

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.

Keywords: N-methylation; Amines; Mechanochemistry; Solvent-free synthesis; Vibrational ball mill.

Abstract

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