In the past few years, continuous-flow reactors with channel dimensions in the micro- or millimeter region have found widespread application in organic synthesis. The characteristic properties of these reactors are their exceptionally fast heat and mass transfer. In microstructured devices of this type, virtually instantaneous mixing can be achieved for all but the fastest reactions. Similarly, the accumulation of heat, formation of hot spots, and dangers of thermal runaways can be prevented. As a result of the small reactor volumes, the overall safety of the process is significantly improved, even when harsh reaction conditions are used. Thus, microreactor technology offers a unique way to perform ultrafast, exothermic reactions, and allows the execution of reactions which proceed via highly unstable or even explosive intermediates. This Review discusses recent literature examples of continuous-flow organic synthesis where hazardous reactions or extreme process windows have been employed, with a focus on applications of relevance to the preparation of pharmaceuticals.

In the not too distant future many industrially important chemicals (including pharmaceuticals) will probably be manufactured using continuous flow technology. For a significant number of synthetic steps involved in these protocols transition metal (mostly palladium)‐catalyzed carbon–carbon or carbon–heteroatom bond forming reactions (“cross‐coupling chemistry”) will play an important role. Designing a process for continuous cross‐coupling chemistry involves either the use of a homogeneous or of a heterogeneous (immobilized) catalyst/ligand system. In the latter case, the catalyst/ligand system is typically in the form of a packed‐bed reactor, through which the reaction mixture is pumped, employing an appropriate temperature regime and residence time. Although this approach has been widely popular during the past 15 years, there is growing evidence that suggests that the use of immobilized transition metal catalysts for performing cross‐coupling chemistry in continuous flow is, in fact, not very practical. As demonstrated in this review, significant leaching of the transition metal out of the packed‐bed catalyst will almost inevitably occur, leading to decreased catalyst activity and contamination of the product with transition metal. This is a consequence of the well‐known fact that the reaction mechanism for these kinds of transformations is (quasi)homogeneous and involves the transformation of a Pd0 species into a (soluble) PdII species. Using an immobilized catalyst in a batch protocol the transient leaching of palladium will not be immediately obvious, as, after completion of the catalytic cycle, Pd0 will typically redeposit onto the support. In contrast, in continuous flow mode, the palladium metal will progressively be “chromatographed” through the packed‐bed catalyst until, ultimately, all palladium will be removed from the support. This effect typically will become only evident when long run experiments are performed. The preferred alternative, in particular for larger scale experiments, is to use a homogeneous (pre)catalyst in combination with an appropriate catalyst recycling technology.

In multistep continuous flowc hemistry,s tudying complex reaction mixtures in real time is as ignificant challenge,but provides an opportunity to enhance reaction understanding and control. We report the integration of four complementary process analytical technology tools (NMR, UV/Vis,IRand UHPLC) in the multistep synthesis of an active pharmaceutical ingredient, mesalazine.T his synthetic route exploits flow processing for nitration, high temperature hydrolysis and hydrogenation reactions,aswell as three inline separations.A dvanced data analysis models were developed (indirect hard modeling,deep learning and partial least squares regression), to quantify the desired products,intermediates and impurities in real time,a tm ultiple points along the synthetic pathway.T he capabilities of the system have been demonstrated by operating both steady state and dynamic experiments and represents as ignificant step forwardi nd ata-driven continuous flow synthesis.

Iron oxide (Fe3O4) nanocrystals generated in situ from an inexpensive and readily available iron source catalyze the reduction of nitroarenes to anilines with unparalleled efficiency. The procedure is chemoselective, avoids the use of precious metals, and can be applied under mild reflux conditions (65 or 80 °C) or using sealed vessel microwave heating in an elevated temperature regime (150 °C). Utilizing microwave conditions, a variety of functionalized anilines have been prepared in nearly quantitative yields within 2-8 min at 150 °C, in a procedure also successfully applied to the reduction of aliphatic nitro compounds and azides. The iron oxide nanoparticles are generated in a colloidal form, resulting in homogeneous solutions suitable for continuous flow processing. Selected examples of anilines of industrial importance have been prepared in a continuous regime using this protocol.