In this work, a modular flow platform was designed and employed in the synthesis of natural products and for two methodology projects. As the established liquid-driven flow shows several disadvantages, in particular the occurrence of dispersion phenomena between solvent and reagent solutions resulting in high reagent losses, the new concept of an argon-driven flow was pursued. In this way, dispersion phenomena were suppressed, opening up new ways for the handling of valuable intermediates in flow on small scale. To avoid common, unsustainable drying protocols of flow reactors, “Schlenk-in-flow” procedures were developed adopting well-established Schlenk techniques to flow chemistry. To realize these concepts, the extensive use of 3D-printing to enable the manufacturing of tailormade equipment turned out as a key technique. As a proof of concept, two intermediates in natural product synthesis were prepared in reproducible yields slightly higher than in batch. In addition, a new method for the site-selective C–H chlorination of (+)-sclareolide by decatungstate catalysis was developed, allowing improved scalability and higher reaction rates in flow. Furthermore, a general method for the synthesis of functionalized ferrocenyl azides and amines was developed in batch and flow. By halogen-lithium exchange of ferrocenyl halides and subsequent trapping with tosyl azide, a variety of ferrocenyl azides was obtained. In flow, the halogen-lithium exchange and the reaction with tosyl azide proceeded significantly faster due to improved mixing. Also, the subsequent thermolysis of ferrocenyl triazene intermediates could be accelerated at elevated temperature in flow as a result of the enhanced heat-transfer in tube reactors, while thermal strain of hazardous ferrocenyl azides could be minimized. Precipitating para-tolyl sulfinates were efficiently kept in turbid flow by utilizing a triphasic flow regime. The advantageous safety and scalability profile of the flow process was demonstrated on gram scale. Using a Staudinger protocol, ferrocenyl azides were reduced in consistently good yields to the corresponding ferrocenyl amines. Employing the flow platform and a selection of the prepared ferrocenyl azides, a protocol for the rapid and scalable synthesis of benzotriazoles via [3+2] cycloaddition of azides and arynes was developed. By making use of the advantages of flow chemistry in the safe handling of potentially explosive azides and the improved reaction control of highly reactive arynes, the process could be performed at elevated temperature providing faster reactions and an increased productivity. The scalability of the flow protocol was demonstrated for the synthesis of an antibacterial and antifungal benzotriazole on gram scale.
