Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• Conrad Kuhwald Sibel Turkhan Andreas Kirschning Institute of Organic Chemistry, Leibniz University Hannover, Schneiderberg 1b, 30167 Hannover, Germany 10.3762/bjoc.18.70 Abstract Inductive heating has developed into a powerful and rapid indirect heating technique used in various fields of

• chemistry, but also in medicine. Traditionally, inductive heating is used in industry, e.g., for heating large metallic objects including bending, bonding, and welding pipes. In addition, inductive heating has emerged as a partner for flow chemistry, both of which are enabling technologies for organic

• synthesis. This report reviews the combination of flow chemistry and inductive heating in industrial settings as well as academic research and demonstrates that the two technologies ideally complement each other. Keywords: catalysis; enabling technologies; flow chemistry; inductive heating; multistep

Assessing the possibilities of designing a unified multistep continuous flow synthesis platform

• Mrityunjay K. Sharma,
• Roopashri B. Acharya,
• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2018, 14, 1917–1936, doi:10.3762/bjoc.14.166

• permeable membrane reactors [46][47][48], high-pressure reactors utilizing back pressure regulators [49][50][51], reactors with different heating and cooling modes (e.g., inductive heating [11][52], microwave [53][54][55] etc.) and many more, also very special reactors [56] with other difficulties that need

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97

• Xantphos as a ligand in an ethyl acetate medium. These reagents are passed through a PEEK reactor filled with 0.8 mm steel beads and were heated at 50 °C by inductive heating (15 kHz). The reaction is subsequently quenched using distilled water and extracted in-line and passed through a silica cartridge to

• over 250 h. The reaction mixture is further mixed with HCl in MeOH/AcOEt and subjected to acid-catalyzed cyclization in a 0.3 mL coiled reactor at 140 °C (inductive heating, 800 kHz). This resulted in 88% overall yield. The isolated product is then mixed with piperazine and passed through the PEEK

• . The mixed stream can then be passed through the packed reactor with the inductive heating system. The induction heating system should actually be coupled with a suitable cooling system to avoid possible uneven spatial heating effects. Alternatively, unless otherwise needed, the conventional heating

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• rely on convective heat transfer. Although this is rapid for small reactor dimensions as the scale of the device increases the efficacy of the heating rapidly falls. The Kirschning group has introduced inductive heating (IH) as an energy stimulus for continuous flow synthesis [102][103]. In this

• application of this new concept was demonstrated in the flow synthesis of the atypical neurolepticum olanzapine (121) [104]. The synthesis begins with a Buchwald–Hartwig coupling between 2-iodonitrobenzene (122) and 2-aminothiophene 123 enabled by inductive heating (Scheme 21). After in-line extraction and

• -methylpiperazine (126) through a final inductively heated reactor containing Ti-doped Magsilica (85 °C, 83% after 15 h processing). Whilst this study did not aim to produce olanzapine at scale it aptly demonstrates the successful development and adaptation of inductive heating to the flow synthesis of this

[3 + 2]-Cycloadditions of nitrile ylides after photoactivation of vinyl azides under flow conditions

• Stephan Cludius-Brandt,
• Lukas Kupracz and
• Andreas Kirschning

Beilstein J. Org. Chem. 2013, 9, 1745–1750, doi:10.3762/bjoc.9.201

• from the corresponding vinyl azide. Keywords: azirines; cycloaddition; flow chemistry; flow reactors; inductive heating; nitrile ylides; photochemistry; vinyl azides; Introduction Recently, photochemistry has seen a renaissance despite the fact that under batch conditions specialized reaction vessels

• azides 1 from alkenes 6 under flow conditions [9]. Schematic presentation of the flow set-up for the synthesis of 2H-azirines 2 under inductive heating (IH, left) and photochemical (hν, right) conditions. Photoinduced cycloadditions of vinyl azides 1a–f and electron-deficient alkenes 4a–d. All

• of 2H-azirines 2 under inductive heating and photochemical conditions. The experiments were conducted at a concentration of 0.05 M. Optimization of the photolysis of vinyl azide 1a and trapping of nitrile ylide with acrylonitrile 4a under flow conditions. Supporting Information Supporting

Multistep flow synthesis of vinyl azides and their use in the copper-catalyzed Huisgen-type cycloaddition under inductive-heating conditions

• Lukas Kupracz,
• Jan Hartwig,
• Jens Wegner,
• Sascha Ceylan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2011, 7, 1441–1448, doi:10.3762/bjoc.7.168

• reactor. Keywords: flow reactor; inductive heating; iodine azide; polymer-supported reagents; vinyl azides; Introduction Azides are highly versatile organic functional groups and their preparation and their reactivity are well explored [1]. In contrast, the synthesis of vinyl azides is far away from

• protocol starts from alkenes, which are transformed by a 1,2-addition of iodine azide and then to the corresponding vinyl azides. Furthermore, for the first time we present the copper-mediated Huisgen-type “click” cycloaddition of vinyl azides with alkynes to yield vinyl triazoles under inductive-heating

Chemistry in flow systems II

• Andreas Kirschning

Beilstein J. Org. Chem. 2011, 7, 1046–1047, doi:10.3762/bjoc.7.119

• , which are difficult to handle in a batch reactor. And third, new heating concepts, including inductive heating, are rendered possible, allowing us to carry out accelerated synthesis under pressure, up to supercritical conditions, but whereby only a small volume of the reaction mixture inside the flow