Solvent Minimized Synthesis of Amides by Reactive Extrusion.

Herein, we report on the translation of a small scale ball-milled amidation protocol into a large scale continuous reactive extrusion process. Critical components to the successful translation were: a) understanding how the different operating parameters of a twin-screw extruder should be harnessed to control prolonged continuous operation, and b) consideration of the physical form of the input materials. The amidation reaction is applied to 36 amides spanning a variety of physical form combinations (liquid-liquid, solid-liquid and solid-solid). Following this learning process, we have developed an understanding for the translation of each physical form combination and demonstrated a 7-hour reactive extrusion process for the synthesis of an amide on 500 gram scale (1.3 mols of product).

Challenges Arising from Continuous-Flow Olefin Metathesis.

The versatility of olefin metathesis is evident from its successful applications ranging from natural product synthesis to the valorization of renewable feedstocks. On the other side, flow chemistry has recently gained particular interest among the synthetic community, offering valuable alternatives to classic batch chemistry and paving the way to the development of new transformations. The application of continuous-flow methods to olefin metathesis represents one of the most promising evolutions in the field at the interface of industrially relevant synthesis and reactor engineering, significantly improving some of the typical problems such as undesired self-reactions and ethylene-mediated catalyst deactivation. This Minireview aims to provide a brief survey covering the major aspects of those techniques which we hope may be of interest for the chemical community as well as those interested in catalysis, continuous processing, enabling technologies and reactor design.

Continuous Flow Generation of Acylketene Intermediates via Nitrogen Extrusion.

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.

Solvent-Minimized Synthesis of 4CzIPN and Related Organic Fluorophores via Ball Milling.

The mechanochemical synthesis of 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile and related organic fluorophores/photocatalysts via a solvent-minimized four-fold SNAr pathway is herein described. Employing sodium tert-butoxide as base, and negating the need for any air/moisture-sensitive reaction set-ups, a selection of organic dyes was synthesized in just 1 h using this ball-milling technique. Furthermore, the transformation was then showcased on a multigram scale.

A Robust Pd-Catalyzed C-S Cross-Coupling Process Enabled by Ball-Milling.

An operationally simple mechanochemical C-S coupling of aryl halides with thiols has been developed. The reaction process operates under benchtop conditions without the requirement for a (dry) solvent, an inert atmosphere, or catalyst preactivation. The reaction is finished within 3 h. The reaction is demonstrated across a broad range of substrates; the inclusion of zinc metal has been found to be critical in some instances, especially for coupling of alkyl thiols.