A scalable and safe continuous flow procedure for in-line generation of diazomethane and its precursor MNU

Abstract

A green approach towards the on-demand in-line generation of MNU and diazomethane in a continuous flow.

The Generation of Diazo Compounds in Continuous‐Flow

“…Different groups further investigated the concept to generate diazo alkanes from nitroso compounds in a continuous‐flow protocol . In 2016, Koolman and co‐workers reported the application of the tube‐in‐tube reactor device in the synthesis of cyclopropyl boronic esters using palladium(II) acetate as the catalyst (Scheme ) …”

“…Important improvements to increase the reaction scale and safety were achieved by Maggini and co‐workers and Lehmann, who reported on applications of N ‐methyl N ‐nitrosourea (MNU, 11 ) in a flow system and subsequent esterification reactions. Maggini et al.…”

“…This marks an important milestone to further improve on reaction safety and minimization of contamination risks of operating personnel (Scheme ). Importantly, this setup can be utilized for the gram‐scale synthesis of methyl esters and features a productivity of 4.9 g h −1 of diazomethane …”

“…[23] Different groups furtheri nvestigated the concept to generate diazo alkanes from nitroso compounds in ac ontinuousflow protocol. [24][25][26] In 2016, Koolman and co-workers reported the applicationo ft he tube-in-tuber eactor device in the synthesis of cyclopropyl boronic esters using palladium(II) acetate as the catalyst (Scheme 4). [24] Important improvements to increase the reactions cale and safety were achieved by Maggini and co-workers [25] and Lehmann, [26] who reported on applicationso fN-methyl N-nitrosourea (MNU, 11)i naf low system and subsequente sterification reactions.…”

“…[24][25][26] In 2016, Koolman and co-workers reported the applicationo ft he tube-in-tuber eactor device in the synthesis of cyclopropyl boronic esters using palladium(II) acetate as the catalyst (Scheme 4). [24] Important improvements to increase the reactions cale and safety were achieved by Maggini and co-workers [25] and Lehmann, [26] who reported on applicationso fN-methyl N-nitrosourea (MNU, 11)i naf low system and subsequente sterification reactions. Maggini et al used aC orning LowFlow or GEN1 modules for the generation of diazomethane (8)f rom MNU (11)u nder alkaline conditions (residence time:2 8sec, reactor volume: 24.98 mL, productivity of diazomethane:u pt o 19 mol d À1 or 33 gh À1 ).…”