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A continuous process for the synthesis and inline separation of anhydrous trifluoromethyl diazomethane in a single continuous flow process is presented. The diazo building block is generated from the corresponding amine and NaNO2 under acidic, aqueous conditions and subsequently diffuses through a gas-permeable membrane into an organic stream. To avoid storage and transportation of the hazardous compound, a representative downstream process in a packed-bed reactor yielding highly functionalized building blocks was developed.

A copper(II)/NafionNR50-catalyzed cascade is demonstrated, wherein in situ keteneimine formation and hydroarylation processes are involved. Various substituted 4-sulfonamidoquinolin-2-ones and various derivatives thereof were obtained. The robust toluenesulfonamide protecting group can be removed on demand in a mild light-promoted process to provide access to otherwise difficult to obtain 4-aminoquinolin-2-ones.

Phosphazenes of vinyldiazocarbonyl compounds having cis stereochemistry of the functional groups on the vinyl bond readily produce pyridazines by a diaza-Wittig process, whereas their counterparts with trans configuration remain intact under similar reaction conditions. Upon UV irradiation trans-phosphazenes furnish pyridazines through a tandem trans-to-cis isomerization followed by intramolecular cyclization. At elevated temperatures trans-(triphenyl)phosphazenes dissociate to give the initial vinyldiazo compounds, which produce pyrazoles in high yields. The first theoretical study on the mechanism of the diaza-Wittig process by DFT calculations at the M06-2X/6-31G(d) level of theory suggest that for the cis-phosphazenes a rapid tandem [2+2] cycloaddition/cycloelimination process with low energy barriers is preferred over trans isomers.

A continuous Bucherer–Bergs hydantoin synthesis utilizing intensified conditions is reported. The methodology is characterized by a two-feed flow approach to independently feed the organic substrate and the aqueous reagent solution. The increased interfacial area of the biphasic reaction mixture and the lack of headspace enabled almost quantitative conversions within ca. 30 minutes at 120 °C and 20 bar even for unpolar starting materials. In addition, a selective N(3)-monoalkylation of the resulting heterocycles under batch microwave conditions is reported yielding potential acetylcholinesterase inhibitors.

Diazo anhydrides (Ar-N=N-O-N=N-Ar) have been known since 1896 but have rarely been used in synthesis. This communication describes the development of a photochemical catalyst-free C-H arylation methodology for the preparation of bi(hetero)aryls by the one-pot reaction of anilines with tert-butyl nitrite and (hetero)arenes under neutral conditions. The key step in this procedure is the in situ formation and subsequent photochemical (>300 nm) homolytic cleavage of a transient diazo anhydride intermediate. The generated aryl radical then efficiently reacts with a (hetero)arene to form the desired bi(hetero)aryls producing only nitrogen, water, and tert-butanol as byproducts. The scope of the reaction for several substituted anilines and (hetero)arenes was investigated. A continuous-flow protocol increasing selectivity and safety has been developed enabling the experimentally straightforward preparation of a variety of substituted bi(hetero)aryls within 45 min of reaction time.

The development of a continuous flow multistep strategy for the synthesis of linear peptoids and their subsequent macrocyclization via click chemistry is described.

The extremely rapid and selective method tolerates multiple functional groups except the ones reacting with the reducing agent, hydrazine.

The presented protocol enables the synthesis of fluorinated benzylic substrates bearing different substituents in short reaction times.

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.

A fully continuous four step process for the preparation of β-amino acids from their corresponding α-amino acids utilizing the Arndt–Eistert homologation approach is described.

A highly efficient continuous flow process for the synthesis of α-halo ketones is reported.

A novel system for the α-trifluoromethylation of carbonyl compounds is used, which combines CF3SO2Cl as a source of CF3 radicals and Eosin Y as a photoredox catalyst.

A continuous-flow protocol for the bromination of benzylic compounds with NBS is presented.

A continuous-flow protocol for the preparation of organic nitriles from carboxylic acids has been developed. The method is based on the acid–nitrile exchange reaction with acetonitrile, used as the solvent, and takes place without any catalyst or additives under the high-temperature/high-pressure conditions employed. At 350 °C and 65 bar, where acetonitrile is in its supercritical state, the transformation of benzoic acid to benzonitrile requires 25 min. The protocol has been tested for a variety of nitriles, including aromatic and aliphatic substrates.

The presented catalyst-free procedure is applicable to several internal and terminal alkenes with high conversions and yields.

A new vertical blade stir bar that improves the stirring performance in flow-constricting microwave vessels is designed and evaluated for several transformations where stirring and efficient agitation are known to be of importance.

This method uses in situ generated highly active Fe3O4 nanocrystals as catalyst and hydrazine as hydrogen source under microwave conditions, thus avoiding the need for a precious metal catalyst and hydrogen gas.

High-speed microwave chemistry has attracted considerable attention in the past two decades with new and innovative applications in organic and peptide synthesis, polymer chemistry, material sciences, nanotechnology and biochemical processes continuously being reported in the literature. In particular the introduction of benchtop single-mode microwave reactors just over ten years ago has revolutionized the way many scientists today perform reactions in the laboratory. Unfortunately, the accurate measurement of reaction temperature in these devices is far from being trivial and requires both a basic understanding of microwave dielectric heating effects and use of appropriate temperature monitoring devices. In this tutorial review frequently occurring problems in the determination of accurate reaction temperatures in single-mode microwave reactors are discussed.

The use of high temperature/pressure gas-liquid continuous flow conditions significantly enhance the iron-catalyzed aerobic oxidation of benzylpyridines (I) to the corresponding ketones (II).

An efficient continuous flow process is elaborated for the methylation of indoles (I), phenols (IV), thiophenols (VI), and carboxylic acids (VIII) using in situ generated tributylmethylammonium methylcarbonate as a catalyst.

The safe and scalable process allows the selective reduction of various functionalized nitroarenes to the corresponding anilines.

The formation of unsymmetrical acetals is smoothly achieved using the title Cu-catalyzed etherification of cyclic ethers (II), (IV) or dimethoxyethane (VI) with phenols (I) or β-keto esters (IX).

By employing high-throughput screening, a rapid determination of suitable catalyst/ligand/base combinations for the title reaction can be performed.

In this review, applications of silicon carbide-based microtiter platforms designed for use in combination with dedicated multimode microwave reactors are described. These platforms are employed not only for the efficient parallel synthesis of compound libraries, but also in the context of high-throughput reaction screening/optimization and a number of other (bio)analytical and biomedical applications. Since the semiconducting plate material (silicon carbide) is strongly microwave absorbing and possesses high thermal conductivity, no temperature gradients across the microtiter plate exist. Therefore, many of the disadvantages experienced in attempting to perform microtiter plate chemistry under conventional microwave conditions can be eliminated. In general, the silicon carbide-based microtiter platforms allow sealed vessel processing (either directly in the well or in glass vials placed into the wells) of volumes ranging from 0.02–3.0 mL at a maximum temperature/pressure limit of 200°C/20 bar. Depending on the specific plate and rotor configuration, a maximum of 80–192 transformations can be carried out in parallel in a single microwave irradiation experiment under strict temperature control. A platform type utilizing HPLC/GC vials as reaction vessels allows analysis directly from the reaction vessel eliminating the need for a transfer step from the reaction to the analysis vial. The latter system is particularly useful for analytical applications as well as reaction optimization/screening.

It is demonstrated that tetrazoles can be readily converted to various biologically interesting 1,3,4-oxadiazoles using anhydrides or acid chlorides under microwaves or continuous flow.

Oxazolines are ring-opened in a very efficient manner by treatment with in situ generated HN3 by using a high-temperature/pressure continuous-flow approach.

Colloidal inorganic nanocrystals stand out as an important class of advanced nanomaterials owing to the flexibility with which their physical-chemical properties can be controlled through size, shape, and compositional engineering in the synthesis stage and the versatility with which they can be implemented into technological applications in fields as diverse as optoelectronics, energy conversion/production, catalysis, and biomedicine. The use of microwave irradiation as a non-classical energy source has become increasingly popular in the preparation of nanocrystals (which generally involves complex and time-consuming processing of molecular precursors in the presence of solvents, ligands and/or surfactants at elevated temperatures). Similar to its now widespread use in organic chemistry, the efficiency of "microwave flash heating" in dramatically reducing overall processing times is one of the main advantages associated with this technique. This Review illustrates microwave-assisted methods that have been developed to synthesize colloidal inorganic nanocrystals and critically evaluates the specific roles that microwave irradiation may play in the formation of these nanomaterials.

The popularity of dedicated microwave reactors in many academic and industrial laboratories has produced a plethora of synthetic protocols that are based on this enabling technology. In the majority of examples, transformations that require several hours when performed using conventional heating under reflux conditions reach completion in a few minutes or even seconds in sealed-vessel, autoclave-type, microwave reactors. However, one severe drawback of microwave chemistry is the difficulty in scaling this technology to a production-scale level. This Concept article demonstrates that this limitation can be overcome by translating batch microwave chemistry to scalable continuous-flow processes. For this purpose, conventionally heated micro- or mesofluidic flow devices fitted with a back-pressure regulator are employed, in which the high temperatures and pressures attainable in a sealed-vessel microwave chemistry batch experiment can be mimicked.

A versatile and rapid microwave-assisted procedure for the palladium-catalyzed direct arylation of heterocycles by aryl bromides and heteroaryl bromides is described. This novel protocol features short coupling times (10-60 min) and low catalyst loadings (1 mol %) and allows the successful arylation of previously unreactive heterocyclic substrates.

The method allows an improved access to various (pyrazolyl)carboxanilides which are inhibitors of transient receptor potential channels.

Microreactor technology and continuous flow processing in general are key features in making organic synthesis both more economical and environmentally friendly. Heterogeneous catalytic hydrogenation reactions under continuous flow conditions offer significant benefits compared to batch processes which are related to the unique gas-liquid-solid triphasic reaction conditions present in these transformations. In this review article recent developments in continuous flow heterogeneous catalytic hydrogenation reactions using molecular hydrogen are summarized. Available flow hydrogenation techniques, reactors, commonly used catalysts and examples of synthetic applications with an emphasis on laboratory-scale flow hydrogenation reactions are presented.

Optimized reaction conditions A) or B) are developed to give diarylmethanols or benzyl alcohols.

High-speed and scalable nickel-catalyzed cross-coupling of arylboronic acids with aryl carbamates and sulfamates is achieved by using sealed-vessel microwave processing.

In situ generation of HN3 from NaN3 and AcOH in a microreactor coupled to an intensified high-temperature/high-pressure flow addition step to nitriles yields tetrazole derivatives in good yields with excellent purities.

Challenging Ru-catalyzed ring-closing metathesis transformations leading to eight-membered-ring systems and Ni- or Co-catalyzed [2+2+2] cyclotrimerizations were evaluated at elevated temperatures applying microwave dielectric heating or conventional thermal heating in order to investigate the role of wall effects. All reactions were conducted in a dedicated reactor setup that allowed accurate internal reaction temperature measurements using fiber-optic probes for both types of heating modes. For ring-closing metathesis best results were achieved using an open vessel−gas sparging protocol in 1,2-dichloroethane at reflux temperature (83 °C), while cyclotrimerizations were performed under sealed vessel conditions in toluene between 80 and 160 °C. For all studied transformations the results achieved in a single-mode microwave reactor could be reproduced by conventional heating in an oil bath by carefully matching the temperature profiles as close as possible during the entire heating and cooling cycle. In con...

Microreactor technology and continuous flow processing in general are key features in making organic synthesis both more economical and environmentally friendly. When preformed under a high-temperature/pressure process intensification regime many transformations originally not considered suitable for flow synthesis owing to long reaction times can be converted into high-speed flow chemistry protocols that can operate at production-scale quantities. This Focus Review summarizes the state of the art in high-temperature/pressure microreactor technology and provides a survey of successful applications of this technique from the recent synthetic organic chemistry literature.

First described almost a decade ago, “click” reactions such as the Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) are widely used today in organic and medicinal chemistry, in the polymer and material science field, and in chemical biology. While most click reactions can be performed at room temperature there are instances where some form of process intensification is required. In this tutorial review, aimed at the synthetic chemistry community, examples of click chemistry carried out under non-classical reaction conditions, such as for example applying microwave heating or continuous flow processing will be highlighted.

Ethyl 2-amino-4-aryl-1,4-dihydro-6-phenylpyrimidine-5-carboxylates readily react, under microwave irradiation and solvent-free conditions, with 3-formylchromone or diethyl (ethoxymethylene)malonate to yield novel pyrimido[1,2-a]pyrimidines. The structure of the final products, deduced from the spectral data and confirmed by X-ray analysis, allows us to suggest reaction pathways.