A continuous-flow protocol for the bromination of benzylic compounds with N-bromosuccinimide (NBS) is presented. The radical reactions were activated with a readily available household compact ...fluorescent lamp (CFL) using a simple flow reactor design based on transparent fluorinated ethylene polymer (FEP) tubing. All of the reactions were carried out using acetonitrile as the solvent, thus avoiding hazardous chlorinated solvents such as CCl4. For each substrate, only 1.05 equiv of NBS was necessary to fully transform the benzylic starting material into the corresponding bromide. The general character of the procedure was demonstrated by brominating a diverse set of 19 substrates containing different functional groups. Good to excellent isolated yields were obtained in all cases. The novel flow protocol can be readily scaled to multigram quantities by operating the reactor for longer time periods (throughput 30 mmol h(-1)), which is not easily possible in batch photochemical reactors. The bromination protocol can also be performed with equal efficiency in a larger flow reactor utilizing a more powerful lamp. For the bromination of phenylacetone as a model, a productivity of 180 mmol h(-1) for the desired bromide was achieved.
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.
Gas–liquid–solid interplay: Heterogeneous catalytic hydrogenation reactions under continuous‐flow conditions offer significant benefits when it comes to sustainability, compared to batch processes. These are related to the unique gas–liquid–solid triphasic reaction conditions present in these systems. In this Review recent developments in continuous‐flow heterogeneous catalytic hydrogenation reactions using molecular hydrogen are summarized.
Diazo anhydrides (ArNNONNAr) have been known since 1896 but have rarely been used in synthesis. This communication describes the development of a photochemical catalyst‐free CH 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.
Simply mix and irradiate: Highly explosive diazo anhydrides (see scheme) are implicated as key intermediates in a photochemical procedure that enables the formation of bi(hetero)aryls by simply mixing anilines with tert‐butyl nitrite and a (hetero)arene under UV light. Using continuous flow technology, a variety of bi(heteroaryl) substrates can be obtained in short reaction times.
The synthesis of many valuable C19 androgens can be accomplished by removal of the C17 side chain from more abundant corticosteroids, followed by further derivatization of the resulting 17‐keto ...derivative. Conventional chemical reagents pose significant drawbacks for this synthetic strategy, as large amounts of waste are generated, and quenching of the reaction mixture and purification of the 17‐ketosteroid intermediate are typically required. Herein, we present mild, safe, and sustainable electrochemical strategies for the preparation of C19 steroids. A reagent and catalyst free protocol for the removal of the C17 side chain of corticosteroids via anodic oxidation has been developed, enabling several one‐pot, multistep procedures for the synthesis of androgen steroids. In addition, simultaneous anodic C17 side chain cleavage and cathodic catalytic hydrogenation of a steroid has been demonstrated, rendering a convenient and highly atom economic procedure for the synthesis of saturated androgens.
Electrochemical manipulation of corticosteroids has enabled the preparation of important C19 steroids via removal of the C17 side chain. The reagent‐free electrochemical method permitted several one‐pot multistep syntheses of androgens. Simultaneous anodic oxidation and cathodic catalytic hydrogenation of corticosteroids for the generation of saturated androgens has also been established.
Mizoroki–Heck couplings of aryl iodides and bromides with butyl acrylate were investigated as model systems to perform transition‐metal‐catalyzed transformations in continuous‐flow mode. As a ...suitable ligandless catalyst system for the Mizoroki–Heck couplings both heterogeneous and homogeneous Pd catalysts (Pd/C and Pd acetate) were considered. In batch mode, full conversion with excellent selectivity for coupling was achieved applying high‐temperature microwave conditions with Pd levels as low as 10−3 mol %. In continuous‐flow mode with Pd/C as a catalyst, significant Pd leaching from the heterogeneous catalyst was observed as these Mizoroki–Heck couplings proceed by a homogeneous mechanism involving soluble Pd colloids/nanoparticles. By applying low levels of Pd acetate as homogeneous Pd precatalyst, successful continuous‐flow Mizoroki–Heck transformations were performed in a high‐temperature/pressure flow reactor. For both aryl iodides and bromides, high isolated product yields of the cinnamic esters were obtained. Mechanistic issues involving the Pd‐catalyzed Mizoroki–Heck reactions are discussed.
Going in a flash! The Mizoroki–Heck synthesis of cinnamic esters by using low levels of Pd catalyst loading can be performed efficiently in a high‐temperature/pressure stainless steel flow reactor (X‐Cube Flash; see scheme).
Molecular oxygen (O
2
) is the ultimate “green” oxidant for organic synthesis. There has been recent intensive research within the synthetic community to develop new selective liquid phase aerobic ...oxidation methodologies as a response to the necessity to reduce the environmental impact of chemical synthesis and manufacture. Green and sustainable chemical processes rely not only on effective chemistry but also on the implementation of reactor technologies that enhance reaction performance and overall safety. Continuous flow reactors have facilitated safer and more efficient utilization of O
2
, whilst enabling protocols to be scalable. In this article, we discuss recent advancements in the utilization of continuous processing for aerobic oxidations. The translation of aerobic oxidation from batch protocols to continuous flow processes, including process intensification (high T/p), is examined. The use of “synthetic air”, typically consisting of less than 10% O
2
in N
2
, is compared to pure O
2
(100% O
2
) as an oxidant source in terms of process efficiency and safety. Examples of homogeneous catalysis and heterogeneous (packed bed) catalysis are provided. The application of flow photoreactors for the in situ formation of singlet oxygen (
1
O
2
) for use in organic reactions, as well as the implementation of membrane technologies, green solvents and recent reactor solutions for handling O
2
are covered.
The Beckmann rearrangement of oximes to amides typically requires strong acids or highly reactive, hazardous electrophiles and/or elevated temperatures to proceed. A very attractive alternative is ...the in situ generation of Vilsmeier–Haack reagents, by means of photoredox catalysis, as promoters for the thermal Beckmann rearrangement. Investigation of the reaction parameters for this light‐induced method using a one‐pot strategy has shown that the reaction is limited by the different temperatures required for each of the two sequential steps. Using a continuous flow reactor, the photochemical and thermal processes have been separated by integrating a flow photoreactor unit at low temperature for the electrophile generation with a second reactor unit, at high temperature, where the rearrangement takes place. This strategy has enabled excellent conversions and yields for a diverse set of oximes, minimizing the formation of side products obtained with the original one‐pot method.
A two‐step sequential process involving a photochemical and a thermal reaction have been carried out in a continuous flow reactor. Separation of the two transformations has enabled their independent operation at different optimal temperatures improving their individual performance and maximizing the overall yield.
In 1893, P. Biginelli reported the synthesis of functionalized 3, 4-dihydropyrimidin-2(1H)-ones (DHPMs) via three-component condensation reaction of an aromatic aldehyde, urea, and ethyl ...acetoacetate. In the past decade, this long-neglected multicomponent reaction has experienced a remarkable revival, mainly due to the interesting pharmacological properties associated with this dihydropyrimidine scaffold. In this Account, we highlight recent developments in the Biginelli reaction in areas such as solid-phase synthesis, combinatorial chemistry, and natural product synthesis.
Dynamic deracemization processes, such as crystallization‐induced diastereomer transformations (CIDTs), offer the opportunity to combine racemization and resolution processes, to provide high yields ...of enantiomerically pure compounds. To date, few of these processes have incorporated photochemical racemization. By combining batch crystallization with a flow photoreactor for efficient irradiation, it is possible to perform such deracemization in an effective, scalable and high yielding manner. After applying design of experiment (DoE) principles and mathematical modelling, the most efficient parameter set could be identified, leading to excellent results in just 4 h reaction time: isolated yield of 82 % and assay ee of 96 %. Such photochemical racemization methods can serve to open new avenues for preparation of enantiomerically pure functional molecules on both small and industrially‐relevant scales.
Photo‐transformation: Unlike classical enantiomeric resolution methods, crystallization‐induced diastereomer transformations (CIDTs) allow full conversion to the desired enantiomer. Using photochemical racemization for a CIDT has not before been published in the scientific literature. We report the use of an oscillatory flow reactor for efficient irradiation, allowing high yield and >95 % ee to be achieved in a reaction time of just a few hours.
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