Diazomethane is among the most versatile and useful reagents for introducing methyl or methylene groups in organic synthesis. However, because of its explosive nature, its generation and purification ...by distillation are accompanied by a certain safety risk. This protocol describes how to construct a configurationally simple tube-in-flask reactor for the in situ on-demand generation of anhydrous diazomethane using membrane separation technology and thus avoiding distillation methods. The described reactor can be prepared from commercially available parts within ∼1 h. In this system, solutions of Diazald and aqueous potassium hydroxide are continuously pumped into a spiral of membrane tubing, and diazomethane is generated upon mixing of the two streams. Pure diazomethane gas diffuses out of the reaction mixture through the membrane tubing (made of gas-permeable Teflon AF-2400). As the membrane tubing is immersed in a flask filled with the substrate solution, diazomethane is instantly consumed, which minimizes the risk of diazomethane accumulation. For this protocol, the reaction of diazomethane with benzoic acid on a 5-mmol scale has been selected as a model reaction and is described in detail. Methyl benzoate was isolated in an 88-90% yield (597-611 mg) within ∼3 h.
Enhanced heat and mass transfer, precise residence time control, shorter process times, increased safety, reproducibility, better product quality and easy scalability are just a few of the advantages ...of flow chemistry and reason for the increasing implementation of continuous processes not only in academia but also into the fine chemical manufacturing sector. Notably, to make a process greener and more sustainable becomes eminently important when going from lab-scale to production scale. In this review, the question to which extent continuous flow processing has an impact as green technology, in particular on the synthesis of active pharmaceutical ingredients (APIs) on manufacturing scale, is discussed. Based on the principles of both green chemistry and green engineering selected continuous processes are evaluated.
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•Green processes need to be scalable to have the greatest environmental impact.•Focus on continuous API synthesis on larger (industrial) scale.•Main drivers for continuous processing: safety, quality, speed, cost.•Benefits of continuous processing to the principles of green processing: maximize efficiency, minimize waste, reduce cost.
The temperature profiles obtained from both an external infrared and internal fiber-optic sensor were compared for heating and synthesizing the ionic liquid 1-butyl-3-methylimidazolium bromide ...(bmimBr) under microwave conditions. Utilizing a single-mode microwave reactor that allows simultaneous infrared/fiber-optic temperature measurements, significant differences between the two methods of temperature monitoring were revealed. Due to the strong microwave absorptivity of ionic liquids and the delay experienced in monitoring temperature on the outer surface of a heavy-walled glass vial, external infrared temperature sensors can not be used to accurately control the temperature in the heating of ionic liquids under microwave conditions. The use of internal fiber-optic probes allows the monitoring and control of the heating behavior in a much better way. In order to prevent the strong exotherm in the synthesis of bmimBr under microwave conditions the use of a reaction vessel made out of silicon carbide is the method of choice. Because of the high thermal conductivity and effusivity of silicon carbide, the heat generated during the ionic liquid formation is efficiently exchanged with the comparatively cool air in the microwave cavity via the silicon carbide ceramic.
One of the rare alternative reagents for the reduction of carbon–carbon double bonds is diimide (HNNH), which can be generated in situ from hydrazine hydrate (N2H4⋅H2O) and O2. Although this ...selective method is extremely clean and powerful, it is rarely used, as the rate‐determining oxidation of hydrazine in the absence of a catalyst is relatively slow using conventional batch protocols. A continuous high‐temperature/high‐pressure methodology dramatically enhances the initial oxidation step, at the same time allowing for a safe and scalable processing of the hazardous reaction mixture. Simple alkenes can be selectively reduced within 10–20 min at 100–120 °C and 20 bar O2 pressure. The development of a multi‐injection reactor platform for the periodic addition of N2H4⋅H2O enables the reduction of less reactive olefins even at lower reaction temperatures. This concept was utilized for the highly selective reduction of artemisinic acid to dihydroartemisinic acid, the precursor molecule for the semisynthesis of the antimalarial drug artemisinin. The industrially relevant reduction was achieved by using four consecutive liquid feeds (of N2H4⋅H2O) and residence time units resulting in a highly selective reduction within approximately 40 min at 60 °C and 20 bar O2 pressure, providing dihydroartemisinic acid in ≥93 % yield and ≥95 % selectivity.
The missing link for a totally continuous transformation of artemisinic acid to a range of antimalarials is the initial olefin reduction in artemisinic acid. It was demonstrated how this transformation can be selectively carried out in continuous flow using in situ generated diimide. Key to the success was the development of a multi‐injection reactor for the consecutive addition of the diimide precursor hydrazine hydrate.
The electron donor‐acceptor complex‐enabled asymmetric photochemical alkylation strategy holds potential to attain elusive chiral α‐alkylated aldehydes without an external photoredox catalyst. The ...photosensitizer‐free conditions are beneficial concerning process costs and sustainability. However, lengthy organocatalyst preparation steps as well as limited productivity and difficult scalability render the current approaches unsuitable for synthesis on enlarged scales. Inspired by these limitations, a protocol was developed for the enantioselective α‐alkylation of aldehydes based on the synergistic combination of visible light‐driven asymmetric organocatalysis and a controlled continuous flow reaction environment. With the aim to reduce process costs, a commercially available chiral catalyst has been exploited to achieve photosensitizer‐free enantioselective α‐alkylations using phenacyl bromide derivates as alkylating agents. As a result of elaborate optimization and process development, the present flow strategy furnishes an accelerated and inherently scalable entry into enantioenriched α‐alkylated aldehydes including a chiral key intermediate of the antirheumatic esonarimod.
High-speed and scalable nickel-catalyzed cross-coupling of arylboronic acids with aryl carbamates and sulfamates is achieved by using sealed-vessel microwave processing.
No catalyst required! A highly efficient, catalyst‐free process to generate diimide in situ from hydrazine monohydrate and molecular oxygen for the selective reduction of alkenes has been developed. ...The use of a gas–liquid segmented flow system allowed safe operating conditions and dramatically enhanced this atom‐economical reaction, resulting in short processing times.
Harnessing hydrazoic acid in a microreactor! Tetrazoles have been synthesized in a very efficient manner by using a high‐temperature/high‐pressure process intensification regime. Despite the toxic ...and explosive nature of hydrazoic acid, the synthesis was conducted safely in continuous flow format with residence times as short as 2.5 minutes at 260 °C (see picture).
