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.

Running oil‐bath chemistry in a microwave! Using reaction vials made out of strongly microwave‐absorbing silicon carbide (SiC) in a microwave reactor simulates experiments conducted in an autoclave with conductive heating because of the efficient shielding of the electromagnetic field by the SiC vial. This technology makes it possible to study the significance of microwave effects.

A continuous process for generation, separation, and reactions of anhydrous diazomethane in a tube-in-tube reactor was developed. The inner tube of the reactor is made of hydrophobic, gas-permeable Teflon AF-2400. The diazomethane is formed in the inner tube and then diffuses through the permeable membrane into the outer chamber and subsequently reacts in the solution carried within. This technique allows safe and scalable reactions with dry diazomethane to be performed on a laboratory scale.

The mechanism of the azide-nitrile cycloaddition mediated by the known dialkylltin oxide-trimethylsilyl azide catalyst system has been addressed through DFT calculations. The catalytic cycle for this tin/silicon complex-based mechanism has been thoroughly examined, disclosing the most plausible intermediates and the energetics involved in the rate enhancement. In addition, a new catalyst, 5-azido-1-methyl-3,4-dihydro-2H-pyrrolium azide, is presented for the formation of tetrazoles by cycloaddition of sodium azide with organic nitriles under neutral conditions. The efficiency of this organocatalyst, generated in situ from N-methyl-2-pyrrolidone (NMP), sodium azide, and trimethylsilyl chloride under reaction conditions, has been examined by preparation of a series of 5-substituted-1H-tetrazoles. The desired target structures were obtained in high yields within 15-25 min employing controlled microwave heating. An in depth computational analysis of the proposed catalytic cycle has also been addressed to understand the nature of the rate acceleration. The computed energy barriers have been compared to the dialkylltin oxide-trimethylsilyl azide metal-based catalyst system. Both the tin/silicon species and the new organocatalyst accelerate the azide-nitrile coupling by activating the nitrile substrate. As compared to the dialkylltin oxide-trimethylsilyl azide method, the organocatalytic system presented herein has the advantage of higher reactivity, in situ generation from inexpensive materials, and low toxicity.

Silicon carbide (SiC) is a strongly microwave absorbing chemically inert ceramic material that can be utilized at extremely high temperatures due to its high melting point and very low thermal expansion coefficient. Microwave irradiation induces a flow of electrons in the semiconducting ceramic that heats the material very efficiently through resistance heating mechanisms. The use of SiC carbide reaction vessels in combination with a single-mode microwave reactor provides an almost complete shielding of the contents inside from the electromagnetic field. Therefore, such experiments do not involve electromagnetic field effects on the chemistry, since the semiconducting ceramic vial effectively prevents microwave irradiation from penetrating the reaction mixture. The involvement of electromagnetic field effects (specific/nonthermal microwave effects) on 21 selected chemical transformations was evaluated by comparing the results obtained in microwave-transparent Pyrex vials with experiments performed in SiC vials at the same reaction temperature. For most of the 21 reactions, the outcome in terms of conversion/purity/product yields using the two different vial types was virtually identical, indicating that the electromagnetic field had no direct influence on the reaction pathway. Due to the high chemical resistance of SiC, reactions involving corrosive reagents can be performed without degradation of the vessel material. Examples include high-temperature fluorine-chlorine exchange reactions using triethylamine trihydrofluoride, and the hydrolysis of nitriles with aqueous potassium hydroxide. The unique combination of high microwave absorptivity, thermal conductivity, and effusivity on the one hand, and excellent temperature, pressure and corrosion resistance on the other hand, makes this material ideal for the fabrication of reaction vessels for use in microwave reactors.

Conspectus In recent years, a steadily growing number of chemists, from both academia and industry, have dedicated their research to the development of continuous flow processes performed in milli- or microreactors. The common availability of continuous flow equipment at virtually all scales and affordable cost has additionally impacted this trend. Furthermore, regulatory agencies such as the United States Food and Drug Administration actively encourage continuous manufacturing of active pharmaceutical ingredients (APIs) with the vision of quality and productivity improvements. That is why the pharmaceutical industry is progressively implementing continuous flow technologies. As a result of the exceptional characteristics of continuous flow reactors such as small reactor volumes and remarkably fast heat and mass transfer, process conditions which need to be avoided in conventional batch syntheses can be safely employed. Thus, continuous operation is particularly advantageous for reactions at high temperatures/pressures (novel process windows) and for ultrafast, exothermic reactions (flash chemistry). In addition to conditions that are outside of the operation range of conventional stirred tank reactors, reagents possessing a high hazard potential and therefore not amenable to batch processing can be safely utilized (forbidden chemistry). Because of the small reactor volumes, risks in case of a failure are minimized. Such hazardous reagents often are low molecular weight compounds, leading generally to the most atom-, time-, and cost-efficient route toward the desired product. Ideally, they are generated from benign, readily available and cheap precursors within the closed environment of the flow reactor on-site on-demand. By doing so, the transport, storage, and handling of those compounds, which impose a certain safety risk especially on a large scale, are circumvented. This strategy also positively impacts the global supply chain dependency, which can be a severe issue, particularly in times of stricter safety regulations or an epidemic. The concept of the in situ production of a hazardous material is generally referred to as the “generator” of the material. Importantly, in an integrated flow process, multiple modules can be assembled consecutively, allowing not only an in-line purification/separation and quenching of the reagent, but also its downstream conversion to a nonhazardous product. For the past decade, research in our group has focused on the continuous generation of hazardous reagents using a range of reactor designs and experimental techniques, particularly toward the synthesis of APIs. In this Account, we therefore introduce chemical generator concepts that have been developed in our laboratories for the production of toxic, explosive, and short-lived reagents. We have defined three different classes of generators depending on the reactivity/stability of the reagents, featuring reagents such as Br 2 , HCN, peracids, diazomethane (CH ...

The development of a continuous flow process for the multistep synthesis of α-halo ketones starting from N-protected amino acids is described. The obtained α-halo ketones are chiral building blocks for the synthesis of HIV protease inhibitors, such as atazanavir and darunavir. The synthesis starts with the formation of a mixed anhydride in a first tubular reactor. The anhydride is subsequently combined with anhydrous diazomethane in a tube-in-tube reactor. The tube-in-tube reactor consists of an inner tube, made from a gas-permeable, hydrophobic material, enclosed in a thick-walled, impermeable outer tube. Diazomethane is generated in the inner tube in an aqueous medium, and anhydrous diazomethane subsequently diffuses through the permeable membrane into the outer chamber. The α-diazo ketone is produced from the mixed anhydride and diazomethane in the outer chamber, and the resulting diazo ketone is finally converted to the halo ketone with anhydrous ethereal hydrogen halide. This method eliminates the need to store, transport, or handle diazomethane and produces α-halo ketone building blocks in a multistep system without racemization in excellent yields. A fully continuous process allowed the synthesis of 1.84 g of α-chloro ketone from the respective N-protected amino acid within ~4.5 h (87% yield).

14-Hydroxymorphinone is converted to noroxymorphone, the immediate precursor of important opioid antagonists, such as naltrexone and naloxone, in a three-step reaction sequence. The initial oxidation of the N-methyl group in 14-hydroxymorphinone with in situ generated colloidal palladium(0) as the catalyst and molecular oxygen as the terminal oxidant constitutes the key transformation in this new route. This oxidation results in the formation of an unexpected oxazolidine ring structure. Subsequent hydrolysis of the oxazolidine under reduced pressure followed by hydrogenation in a packed-bed flow reactor using palladium(0) as the catalyst provides noroxymorphone in high purity and good overall yield. To overcome challenges associated with gas-liquid reactions with molecular oxygen, the key oxidation reaction was translated to a continuous-flow process.