Scalable On-Demand Production of Purified Diazomethane Suitable for Sensitive Catalytic Reactions

We have developed a convenient development-scale reactor (0.44 mol/h) to prepare diazomethane from N-methyl-N-nitroso-p-toluenesulfonamide (MNTS) in ∼80% yield. Diazomethane (CH2N2) made with this reactor is extracted into nitrogen gas from the liquid reaction mixture, effectively removing it from reagents and byproducts that may interfere in subsequent reactions. Vertically oriented tubular reactors were used to produce and consume diazomethane in situ. Key features of this reactor include high productivity and correspondingly low reactor volume (reactor volume/liquid flow rate = 6.5 min) and a commercially available gas/liquid separator equipped with a selectively permeating hydrophilic membrane. The design of the reactor keeps the inventory below 53 mg of CH2N2 during normal operation. The reactor was demonstrated by generating CH2N2 that was used in a connected continuous reactor. We evaluated esterification reactions and a continuous Pd-catalyzed cyclopropanation reaction with the reactor and achieved high conversion with 1.5 and 4.1 equiv of MNTS precursor, respectively.