Copper-Catalyzed, Aerobic Oxidation of Hydrazone in a Three-Phase Packed Bed Reactor

Abstract

Copper-catalyzed, aerobic hydrazone oxidation to produce synthetically useful diazo compounds is achieved in a continuous, three-phase flow reactor with complete conversion and high selectivity by adapting a previously published batch methodology to a flow system described herein and conducting a parameter space exploration to optimize the process conditions. The robust nature of the process is demonstrated, with complete hydrazone conversion and a 90% steady-state diazo compound selectivity maintained over 11 residence times. Employing the diazo synthesis upstream of a limited scope of dirhodium(II)catalyzed carbene reactions demonstrates the utility of this process in generating on-demand diazo compounds for cycloaddition and activated secondary C−H insertion reactions. The resulting process represents, to the best of our knowledge, the first reported catalytic process for hydrazone oxidation in flow. Additionally, this process, which only generates water as an oxidative byproduct, is an improvement over previous noncatalytic attempts to synthesize diazo compounds in flow, which generate stoichiometric amounts of waste. The increased sustainability and mitigation of safety hazards associated with handling reactive diazo compounds may make this approach suitable for practical applications.

Carbene reactivity from alkyl and aryl aldehydes

“…3C): p bond cycloaddition (54 to 56) and s bond insertion (57 and 58). We expect this formaldehyde-based approach to provide a safer alternative to conventional diazomethane reactivity and to complement modern methods that entail in situ generation (7)(8)(9).…”

“…Given the strong entropic and enthalpic driving forces inherent in the release of N 2 from these reagents, strict precautions are necessary to prevent explosive, uncontrolled chain reactions ( 6 ). Strategies to address this underlying safety issue include flow chemistry and in situ diazotization ( 7 – 9 ). Carbonyl and arene stabilizing groups are also frequently used ( 10 ), which influence carbene polarity and selectivity ( 11 , 12 ).…”

Copper(II) Acetate-Induced Oxidation of Hydrazones to Diazo Compounds under Flow Conditions Followed by Dirhodium-Catalyzed Enantioselective Cyclopropanation Reactions

“…35 Having established the batch reaction, we are now developing flow methods for the synthesis of the aryldiazoacetates. We are interested in two distinct applications, a process potentially amenable for industrial scale 36 and a technically simpler labtop procedure.…”

“…The process avoids the engineering challenges of regeneration of the copper(II) salt using air as the terminal oxidant, although a process using copper in catalytic amounts may be required for a practical industrial-scale process. 36…”

“…It requires introduction of the hydrazone at the top of the column without the need to concentrate or isolate the formed diazo compound before the subsequent carbene reaction. The process avoids the engineering challenges of regeneration of the copper­(II) salt using air as the terminal oxidant, although a process using copper in catalytic amounts may be required for a practical industrial-scale process …”