Solvent Minimized Synthesis of Amides by Reactive Extrusion

• Published in: Angewandte Chemie International Edition 2024-10, Vol.63 (41), p.e202408315-n/a
• Main Authors: Bolt, Robert R. A., Smallman, Harry R., Leitch, Jamie A., Bluck, Gavin W., Barreteau, Fabien, Iosub, Andrei V., Constable, David, Dapremont, Olivier, Richardson, Paul, Browne, Duncan L.
• Format: Article
• Language: English
• Subjects: Amides; Continuous extrusion; continuous flow; Critical components; direct amidation; green chemistry; mechanochemistry; solvent-minimised; Synthesis; Translation; twin-screw extrusion
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202408315

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). The direct amidation of esters is converted from a ball‐milled process into a continuous solvent‐minimised reactive extrusion protocol capable of delivering 500 grams (1.3 mols) of amide product over a continuous operation for 7 hours. Key to this, was translation of heating profiles used for the ball‐milling study directly to the extruder and consideration of the physical form of input substrates.