Continuous Platform To Generate Nitroalkanes On-Demand (in Situ) Using Peracetic Acid-Mediated Oxidation in a PFA Pipes-in-Series Reactor

The synthetic utility of the aza-Henry reaction can be diminished on scale by potential hazards associated with the use of peracid to prepare nitroalkane substrates and the nitroalkanes themselves. In response, a continuous and scalable chemistry platform to prepare aliphatic nitroalkanes on-demand using the oxidation of oximes with peracetic acid and direct reaction of the nitroalkane intermediate in an aza-Henry reaction is reported. A uniquely designed pipes-in-series plug-flow tube reactor addresses a range of process challenges, including stability and safe handling of peroxides and nitroalkanes. The subsequent continuous extraction generates a solution of purified nitroalkane, which can be directly used in the following enantioselective aza-Henry chemistry to furnish valuable chiral diamine precursors with high selectivity, thus completely avoiding isolation of the potentially unsafe low-molecular-weight nitroalkane intermediate. A continuous campaign (16 h) established that these conditions were effective in processing 100 g of the oxime and furnishing 1.4 L of nitroalkane solution

Development of an Intermittent-Flow Enantioselective Aza-Henry Reaction Using an Arylnitromethane and Homogeneous Brønsted Acid–Base Catalyst with Recycle

A stereoselective aza-Henry reaction between an arylnitromethane and Boc-protected aryl aldimine using a homogeneous Brønsted acid–base catalyst was translated from batch format to an automated intermittent-flow process. This work demonstrates the advantages of a novel intermittent-flow setup with product crystallization and slow reagent addition which is not amenable to the standard continuous equipment: plug flow tube reactor (PFR) or continuous stirred tank reactor (CSTR). A significant benefit of this strategy was the integration of an organocatalytic enantioselective reaction with straightforward product separation, including recycle of the catalyst, resulting in increased intensity of the process by maintaining high catalyst concentration in the reactor. A continuous campaign confirmed that these conditions could effectively provide high throughput of material using an automated system while maintaining high selectivity, thereby addressing nitroalkane safety and minimizing catalyst usage