Modern flow chemistry – prospect and advantage

• Philipp Heretsch

Beilstein J. Org. Chem. 2023, 19, 33–35, doi:10.3762/bjoc.19.3

• , agrochemicals, fragrances, and many more. Implementation of new and innovative technologies has played a vital role in this mission and has contributed to the opening of new research areas and to pushing the frontiers of existing ones. Among these new technologies, continuous flow chemistry has stepped on the

• chemicals. This has again led to improved scalability, higher purity of products, and eventually decreased manufacturing costs. From the undisputed role of continuous flow chemistry for process chemists, the advent of this technology in academic research laboratories, especially for method development and

• application of continuous flow technology for academic research, leading to an expansion of synthetic options and generally more sustainable operations. Among the many advantages of performing organic reactions in continuous flow, enhanced heat-, mass- and photon transfer, an improved safety profile, broad

Two-step continuous-flow synthesis of 6-membered cyclic iodonium salts via anodic oxidation

• Julian Spils,
• Thomas Wirth and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2023, 19, 27–32, doi:10.3762/bjoc.19.2

• continuous-flow procedure for the generation of six-membered diaryliodonium salts. The accompanying scalability and atom economy are significant improvements to existing batch methods. Benzyl acetates are submitted to this two-step procedure as highly available and cheap starting materials. An acid-catalyzed

• . Conclusion In summary, we have developed the first multi-step continuous-flow procedure for the generation of cyclic six-membered diaryliodonium salts. Starting from easily accessible benzyl acetates we were able to combine a Friedel–Crafts alkylation with a subsequent anodic oxidative cyclization in flow

Inline purification in continuous flow synthesis – opportunities and challenges

• Jorge García-Lacuna and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 1720–1740, doi:10.3762/bjoc.18.182

• Jorge Garcia-Lacuna Marcus Baumann School of Chemistry, University College Dublin, Science Centre South, Belfield, Dublin 4, Dublin, Ireland 10.3762/bjoc.18.182 Abstract Continuous flow technology has become the method of choice for many academic and industrial researchers when developing new

• chemistry tools developed in academia. Keywords: flow synthesis; inline purification; process development; reaction telescoping; scale-up; Introduction Continuous flow chemistry is a mature and widely applied platform technology that exploits intrinsic advantages over batch processing such as better heat

• , chemists can choose from a variety of tools when developing continuous flow experiments, however, more sophisticated flow processes are more complex in nature and will require additional tools and control points to ensure the success of a given campaign. The integration of inline analysis techniques is

Heterogeneous metallaphotoredox catalysis in a continuous-flow packed-bed reactor

• Wei-Hsin Hsu,
• Susanne Reischauer,
• Peter H. Seeberger,
• Bartholomäus Pieber and
• Dario Cambié

Beilstein J. Org. Chem. 2022, 18, 1123–1130, doi:10.3762/bjoc.18.115

• and scalable reaction conditions. Here, we report a continuous-flow approach to metallaphotoredox catalysis using a heterogeneous catalyst that combines the function of a photo- and a nickel catalyst in a single material. The catalyst is embedded in a packed-bed reactor to combine reaction and

• (catalyst) separation in one step. The use of a packed bed simplifies the translation of optimized batch reaction conditions to continuous flow, as the only components present in the reaction mixture are the substrate and a base. The metallaphotoredox cross-coupling of sulfinates with aryl halides was used

• [4][5]. This is underlined by several photochemical and photocatalytic transformations that have been performed on industrial scales in continuous-flow reactors [6][7][8]. A particularly appealing branch of photocatalytic organic synthesis is the combination with other modes of catalysis in dual

First example of organocatalysis by cathodic N-heterocyclic carbene generation and accumulation using a divided electrochemical flow cell

• Daniele Rocco,
• Ana A. Folgueiras-Amador,
• Richard C. D. Brown and
• Marta Feroci

Beilstein J. Org. Chem. 2022, 18, 979–990, doi:10.3762/bjoc.18.98

• membrane, under N2 atmosphere, at room temperature, under galvanostatic conditions (I = 134 mA) with continuous flow rate of 36 mL/min, studying the effect of cathode material, anode solution and number of Faradays per mole of IL supplied (Table 1). At the end of the electrolysis, excess elemental sulfur

• in a continuous flow electrochemical process, the flow methodology was applied to the self-annulation of cinnamaldehyde, a classical NHC-catalyzed reaction (Scheme 4). All the experiments were carried out using a solution of 0.1 M BMImBF4 in acetonitrile (20 mL) as catholyte, stainless steel as

Continuous flow synthesis of azobenzenes via Baeyer–Mills reaction

• Jan H. Griwatz,
• Anne Kunz and
• Hermann A. Wegner

Beilstein J. Org. Chem. 2022, 18, 781–787, doi:10.3762/bjoc.18.78

• used Baeyer–Mills coupling reaction was adopted to a continuous flow setup. The versatility was demonstrated with a scope of 20 substances and the scalability of this method exemplified by the synthesis of >70 g of an azobenzene derivative applied in molecular solar thermal storage (MOST) systems

• . Keywords: azobenzenes; Baeyer–Mills reaction; continuous flow; molecular switches; solar fuel; Introduction Although the red-colored azobenzenes (AB) have been known for years as dyes, their applications nowadays span from energy and information storage [1][2][3][4][5], organocatalysis [6], photobiology

• the proposed mechanism, which involves nucleophilic attack of the aniline on the nitrosobenzene derivatives in acidic or basic media (Scheme 1) [18][19][20][21]. However, in order to use azobenzenes as functional materials, access to a large-scale process is necessary. In this context continuous flow

Synthesis of odorants in flow and their applications in perfumery

• Merlin Kleoff,
• Paul Kiler and
• Philipp Heretsch

Beilstein J. Org. Chem. 2022, 18, 754–768, doi:10.3762/bjoc.18.76

• , Germany 10.3762/bjoc.18.76 Abstract Continuous flow technology is a key technology for sustainable manufacturing with numerous applications for the synthesis of fine chemicals. In recent years, the preparation of odorants utilizing the advantages of flow reactors received growing attention. In this

• “has a pleasant, fresh-citrusy, and peppery-woody odor with a discretely mint note” [9]. Very recently, Kobayashi, Ishitani, and co-workers described a three-step sequential continuous flow process for the synthesis of (S)-α-phellandrene (30) from (R)-carvone (25, Scheme 6) [36]. In the first step, a

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• is important not only in the context of energy storage, CO2 reduction, and climate change prevention, but also because they provide a country-independent source of energy. However, for use in a continuous flow system, the catalyst must have extremely high SAR and catalytic activity. Recently, a

• mesoflow technology and indirect heating 3.1 Microwave-accelerated reactions under flow conditions Reactions that take 20 minutes or longer under classical batch conditions can be accelerated considerably under continuous flow conditions by rapid heating, because flow chemistry usually involves the use of

• dioxide (core-shell nanostructured particles), called MagSilicaTM to be used as fixed-bed materials in many different continuous flow processes (Figure 4A) [50]. These materials are excited very rapidly in a medium frequency (25 kHz) electromagnetic field, heating reaction mixtures in packed bed reactors

Rapid gas–liquid reaction in flow. Continuous synthesis and production of cyclohexene oxide

• Kyoko Mandai,
• Tetsuya Yamamoto,
• Hiroki Mandai and
• Aiichiro Nagaki

Beilstein J. Org. Chem. 2022, 18, 660–668, doi:10.3762/bjoc.18.67

• Medical Science, Nijigaoka, Kani-city, Gifu Prefecture, 509-0293, Japan 10.3762/bjoc.18.67 Abstract The enhanced reaction rate in the epoxidation of cyclohexene with air as an oxidant was discovered without any added catalyst utilizing a continuous flow reactor constructed with readily available

• stainless steel parts and devices. This continuous-flow process demonstrates a significant improvement in reaction time for highly selective epoxide production over the batch process due to the efficient mass transfer between the liquid phase and air. The flow process discovered was operated continuously

• with good operational stability, evaluated by a constant high yield of cyclohexene oxide, to obtain the desired product with high productivity. Keywords: air; continuous flow; cyclohexene oxide; flow epoxidation; rapid gas–liquid reaction; Introduction From the past to the present, organic synthesis

Shift of the reaction equilibrium at high pressure in the continuous synthesis of neuraminic acid

• Jannis A. Reich,
• Miriam Aßmann,
• Kristin Hölting,
• Paul Bubenheim,
• Jürgen Kuballa and
• Andreas Liese

Beilstein J. Org. Chem. 2022, 18, 567–579, doi:10.3762/bjoc.18.59

• Abstract The importance of a compound that helps fight against influenza is, in times of a pandemic, self-evident. In order to produce these compounds in vast quantities, many researchers consider continuous flow reactors in chemical industry as next stepping stone for large scale production. For these

• recycling steps, and were characterized regarding the reaction kinetics (initial rate) and scalability (different lab scales) in a batch reactor. The reaction kinetics were studied in a continuous flow reactor. A high-pressure circular reactor (up to 130 MPa) was applied for the investigation of changes in

Synthesis of piperidine and pyrrolidine derivatives by electroreductive cyclization of imine with terminal dihaloalkanes in a flow microreactor

• Yuki Naito,
• Naoki Shida and
• Mahito Atobe

Beilstein J. Org. Chem. 2022, 18, 350–359, doi:10.3762/bjoc.18.39

• determined (Figure 3). Continuous flow electrolysis could be performed without any problem at least until the fifth fraction collection. The yields of the fractions were almost the same, and the average yield of the five fractions was 77%. In addition, no precipitates were observed on the electrodes after

• American Chemical Society. This content is not subject to CC BY 4.0. Yield of 3a for each fraction sample in the continuous flow reductive cyclization. Conventional synthetic routes for piperidine derivatives. Synthesis of 1,2-diphenylpiperidine (3a) by the electroreductive cyclization mechanism. Effect of

Flow synthesis of oxadiazoles coupled with sequential in-line extraction and chromatography

• Kian Donnelly and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 232–239, doi:10.3762/bjoc.18.27

• Kian Donnelly Marcus Baumann School of Chemistry, University College Dublin, Science Centre South, Belfield, Dublin 4, Ireland 10.3762/bjoc.18.27 Abstract An efficient continuous flow process is reported for the synthesis of various 1,3,4-oxadiazoles via an iodine-mediated oxidative cyclisation

• the ability to improve reaction efficiency, safety and provide access to chemistry that was not previously possible [9][10][11]. Carrying out a reaction in continuous flow mode can improve its efficiency in several ways, including decreasing reaction times, increasing yields, or eliminating tedious

• significant development in continuous flow platforms, particularly in industry [16][17][18][19][20]. 1,3,4-Oxadiazoles are biologically relevant 5-membered heterocyclic compounds with various favourable pharmacokinetic properties and have been investigated as potential candidates for antiviral, antifungal and

1,2-Naphthoquinone-4-sulfonic acid salts in organic synthesis

• Ruan Carlos B. Ribeiro,
• Patricia G. Ferreira,
• Amanda de A. Borges,
• Luana da S. M. Forezi,
• Fernando de Carvalho da Silva and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 53–69, doi:10.3762/bjoc.18.5

• addition, several authors concluded that this was a good method for analytically determining low levels of activated aromatic amines in drugs. This method continued to be used over the years and was subsequently optimized by a spectrophotometric determination technique coupled with continuous flow [55]. In

Electrocatalytic C(sp³)–H/C(sp)–H cross-coupling in continuous flow through TEMPO/copper relay catalysis

• Bin Guo and
• Hai-Chao Xu

Beilstein J. Org. Chem. 2021, 17, 2650–2656, doi:10.3762/bjoc.17.178

• terminal alkynes has been achieved in a continuous-flow microreactor through 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)/copper relay catalysis. The reaction is easily scalable and requires low concentration of supporting electrolyte and no external chemical oxidants or ligands, providing straightforward

• and sustainable access to 2-functionalized tetrahydroisoquinolines. Keywords: continuous flow; copper; catalysis; dehydrogenative cross-coupling; electrochemistry; Introduction The dehydrogenative cross-coupling of two C–H bonds represents an ideal strategy for the construction of C–C bonds [1][2

• reaction of tetrahydroisoquinolines with terminal alkynes (Scheme 1C) [10]. The chiral ligand was found to be critical for the stereoinduction as well as product formation for these electrochemical reactions that are conducted in batch. Continuous-flow electrochemical microreactors offer several advantages

Photoredox catalysis in nickel-catalyzed C–H functionalization

• Lusina Mantry,
• Rajaram Maayuri,
• Vikash Kumar and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2021, 17, 2209–2259, doi:10.3762/bjoc.17.143

• process in a continuous-flow reactor. The mechanistic studies indicated that a nickel hydride intermediate generated with C(sp3)–H as the hydride source is involved in this catalytic transformation. The hydronickelation step results in the sterically less hindered vinylnickel intermediate 15-I, which

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• temperatures, fragrance ingredients/intermediates make ideal candidates for continuous-flow manufacturing. This review highlights the potential crossover between a multibillion dollar industry and the flourishing sub-field of flow chemistry evolving within the discipline of organic synthesis. This is

• investment to maintain and operate (requirements for large volumes of solvent during work-ups and cleaning of reactors between processes). Alternatively, in the continuous-flow approach, a fully automated reaction system can be assembled, in which, transformations occur within reactors with a continuous

• flow [86]. Due to the inherently low active volumes of reactants that are processed in the reaction zone within a continuous-flow reactor, the safety risks associated with critical event are greatly diminished. In addition, process reliance and sustainability are further improved by adding extra safety

Recent advances in palladium-catalysed asymmetric 1,4–additions of arylboronic acids to conjugated enones and chromones

• Jan Bartáček,
• Jan Svoboda,
• Martin Kocúrik,
• Jaroslav Pochobradský,
• Alexander Čegan,
• Miloš Sedlák and
• Jiří Váňa

Beilstein J. Org. Chem. 2021, 17, 1048–1085, doi:10.3762/bjoc.17.84

• , continuous-flow reactions are currently a general challenge, especially for the pharmaceutical industry. The prerequisite for a successful continuous synthesis in the field of asymmetric addition reactions to enones is the mastery of recyclable heterogeneous catalysis. Very recently, we reported [57] the

• is another challenging task. Nevertheless, it should be noted at this point that in the case of rhodium complex catalysis, the asymmetric addition of phenylboronic acid to enones in continuous flow has been successful [24]. In 2021, Walhers et al. presented a theoretical study based on the Q2MM

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• seems to be compromised imposing restrictions on using microwaves at a scale-up level. However, the batch process and continuous flow process seem to provide an entry into scale-up standards with safety. The microwave reactors serving the purpose of batch and parallel approach are designed in various

Synthesis of trifluoromethyl ketones by nucleophilic trifluoromethylation of esters under a fluoroform/KHMDS/triglyme system

• Yamato Fujihira,
• Yumeng Liang,
• Makoto Ono,
• Kazuki Hirano,
• Takumi Kagawa and
• Norio Shibata

Beilstein J. Org. Chem. 2021, 17, 431–438, doi:10.3762/bjoc.17.39

• equivalents of KHMDS. Further application of this “batch protocol” for a “continuous-flow microreactor” reaction is now ongoing in our laboratory towards industrial collaboration. Experimental A test tube containing 1 (0.4 mmol) in triglyme (0.7 mL) was charged with HCF3 (9.9 mL, 1.1 equiv, measured by a

Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivatives

• Alexander Leslie,
• Thomas S. Moody,
• Megan Smyth,
• Scott Wharry and
• Marcus Baumann

Beilstein J. Org. Chem. 2021, 17, 379–384, doi:10.3762/bjoc.17.33

• within continuous flow processes [17][18][19][20] to provide a greener and more chemoselective means for the synthesis of drug-like targets. Recently, we reported on an innovative telescoped process using immobilized CALB (Candida antarctica lipase B) to enable the conversion of residual benzyl alcohol

• into benzyl butyrate in view of facilitating the downstream purification of continuous flow Curtius rearrangement reactions [21]. In this paper, we will give a full account on this valuable approach and showcase the utility of the carbamate products towards generating sets of β-amino acid species

• innovative approach (85% yield, for details see [21]). To further exploit the value of this continuous flow approach the possibility of converting selected carbamate products into derivatives of β-amino acids (e.g., 8) was evaluated. Although this may be achieved by a conventional alkylation of the carbamate

A sustainable strategy for the straightforward preparation of 2H-azirines and highly functionalized NH-aziridines from vinyl azides using a single solvent flow-batch approach

• Michael Andresini,
• Leonardo Degannaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2021, 17, 203–209, doi:10.3762/bjoc.17.20

• risks [6]. Recently, a variety of sustainable solvents has been therefore identified, and their use have been combined with those of enabling technologies. In this scenario, the development of continuous flow synthetic methodologies has found its fortune in the past two decades [7][8][9]. Several

• ]. Similarly, Maurya developed a microfluidic photoreactor for the synthesis of a fused β-carboline from an α-ketovinyl azide and a 1,2,3,4-tetrahydro-β-carboline (Scheme 1b) [30]. More recently, Kappe reported the generation of 2H-azirines under continuous flow conditions, and their transformation into

• ]. Subsequently, the process was examined under continuous flow conditions employing a special integrated coil reactor with two different operating temperatures (see Supporting Information File 1). A solution of 1-(1-azidovinyl)-4-methylbenzene (1a, 0.25 M in CPME) was introduced, via a high pressure syringe pump

Dawn of a new era in industrial photochemistry: the scale-up of micro- and mesostructured photoreactors

• Emine Kayahan,
• Mathias Jacobs,
• Leen Braeken,
• Leen C.J. Thomassen,
• Simon Kuhn,
• Tom van Gerven and
• M. Enis Leblebici

Beilstein J. Org. Chem. 2020, 16, 2484–2504, doi:10.3762/bjoc.16.202

• designing multiphase photoreactors, and this complicates the design even further [10]. Photoreactions are typically performed in batch reactors. With the process intensification efforts towards green chemistry approaches, continuous flow technologies, micro- and mesostructured flow photoreactors having

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

• Shahboz Yakubov and
• Joshua P. Barham

Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

• to the 83% yield under the standard conditions. This reaction was also demonstrated in continuous flow under similar conditions [139]. 3.2 Polarity matching-guided unactivated C(sp3)–H fluorination 3.2.1 Synthetic applications: In another seminal paper, Tan and co-workers [198] discovered the

Synergy between supported ionic liquid-like phases and immobilized palladium N-heterocyclic carbene–phosphine complexes for the Negishi reaction under flow conditions

• Edgar Peris,
• Raúl Porcar,
• María Macia,
• Jesús Alcázar,
• Eduardo García-Verdugo and
• Santiago V. Luis

Beilstein J. Org. Chem. 2020, 16, 1924–1935, doi:10.3762/bjoc.16.159

• , Janssen-Cilag, S.A., C/ Jarama 75A, Toledo, Spain 10.3762/bjoc.16.159 Abstract The combination of supported ionic liquids and immobilized NHC–Pd–RuPhos led to active and more stable systems for the Negishi reaction under continuous flow conditions than those solely based on NHC–Pd–RuPhos. The fine tuning

• under continuous flow conditions. Results and Discussion Scheme 1 summarizes the synthetic approach used for the preparation of the functionalized polymers considered in this work. A commercially available PS-DVB bead-type macroporous chloromethylated polymer 1 (Merrifield resin with 20% DVB and 1.2

• palladium species as calculated by ICP–MS of the respective solutions (>15 ppm of Pd). The elemental analysis of the catalyst after its use was also consistent with this Pd loss from the NHC complex. Additionally, the catalyst 8a was also tested under continuous flow conditions. Although, this time a

When metal-catalyzed C–H functionalization meets visible-light photocatalysis

• Lucas Guillemard and
• Joanna Wencel-Delord

Beilstein J. Org. Chem. 2020, 16, 1754–1804, doi:10.3762/bjoc.16.147

• photochemical reactions due to the inherent lack of scalability issues as a consequence of the Beer–Lambert law of absorption. Consequently, continuous-flow chemistry represents one of the few ways in which pharmaceutically relevant quantities of compounds can be synthesized through photoinduced transformations

• ]. Targeting more sustainable protocols, a manganese catalyst was selected to trigger the coupling between an aryldiazonium salt and simple (hetero)aryls. A unique reactivity was obtained under irradiation with blue LEDs and a continuous-flow process allowed achieving higher reactivity. Under the optimized

• heteroarene coupling partners. Indeed, furans, thiophenes, and pyrroles underwent selectively the non-directed C–H functionalization, delivering a diversity of heteroaryl–aryl coupling products. Remarkably, the continuous-flow technique rendered this transformation perfectly suited for large-scale and rapid