Continuous Flow Generation of Acylketene Intermediates via Nitrogen Extrusion

Abstract

A flow chemistry process for the generation and use of acylketene precursors through extrusion of nitrogen gas is reported. Key to the development of a suitable continuous protocol is the balance of reaction concentration against pressure in the flow reactor. The resulting process enables access to intercepted acylketene scaffolds using volatile amine nucleophiles and has been demonstrated on the gram scale. Thermal gravimetric analysis was used to guide the temperature set point of the reactor coils for a variety of acyl ketene precursors. The simultaneous generation and reaction of two reactive intermediates (both derived from nitrogen extrusion) is demonstrated.

Continuous-Flow Technology for Chemical Rearrangements: A Powerful Tool to Generate Pharmaceutically Relevant Compounds

“…In 2022, Browne and co-workers 22 reported a flow protocol for the generation of acylketene precursors. After the development of a library, the authors also demonstrated the generation and combination of two intermediates via nitrogen extrusion (Scheme 7A), synthesizing an isocyanate in situ through CR.…”