Red light excitation: illuminating photocatalysis in a new spectrum

• Lucas Fortier,
• Corentin Lefebvre and
• Norbert Hoffmann

Beilstein J. Org. Chem. 2025, 21, 296–326, doi:10.3762/bjoc.21.22

• to give 22. In a same manner, Opatz et al. have shown that zinc phthalocyanins can catalyze oxidative cyanation reactions of tertiary amines 23, yielding α-aminonitriles 24 under continuous-flow conditions [36]. This reaction proceeds through the excitation of zinc phthalocyanin by near-infrared

• in continuous-flow conditions. This performance is particularly notable given that the reaction was carried out using sub-part-per-million loadings of the catalyst (0.003 mol %), a stark contrast to traditional systems, which often require higher concentrations of heavy metals. Unlike classical

• integrity over extended reaction times, even under high substrate concentrations and continuous flow conditions, achieving high turnover numbers of over 50000. This stability allowed for solvent-free reactions, significantly enhancing the sustainability of the process. Additionally, the authors have

Recent advances in electrochemical copper catalysis for modern organic synthesis

• Yemin Kim and
• Won Jun Jang

Beilstein J. Org. Chem. 2025, 21, 155–178, doi:10.3762/bjoc.21.9

• group developed the electrocatalytic racemic C(sp³)–H alkynylation of THIQs with terminal alkynes in a continuous-flow microreactor using copper/TEMPO relay catalysis [51]. The electrocatalytic reaction in continuous flow facilitates straightforward scale-up and demonstrating a broad substrate scope. In

Emerging trends in the optimization of organic synthesis through high-throughput tools and machine learning

• Pablo Quijano Velasco,
• Kedar Hippalgaonkar and
• Balamurugan Ramalingam

Beilstein J. Org. Chem. 2025, 21, 10–38, doi:10.3762/bjoc.21.3

• were explored, using a total volume of 4.5 mL reaction mixture, and the screening results can be readily translated to continuous flow synthesis. The application of segmented flow or microslug reactors was demonstrated in the decarboxylative arylation cross-coupling reaction promoted by catalysts and

• heterogeneous solid–liquid reactions. In their report, they described the reaction slugs as serial microbatch reactors (SMBRs) separated through gas segments that incorporated liquid reagents and solid photocatalysts in a continuous flow. The slugs were generated by establishing a stable gas–liquid segmented

• . Photochemical reactions require uniform light penetration of the reaction mixture, and flow setups with uniform path lengths would be ideal for such reactions. A self-optimizing continuous-flow reactor was designed by Poscharny et al. [59] for [2 + 2]-cycloaddition reactions promoted by light. The optimization

Advances in the use of metal-free tetrapyrrolic macrocycles as catalysts

• Mandeep K. Chahal

Beilstein J. Org. Chem. 2024, 20, 3085–3112, doi:10.3762/bjoc.20.257

• of enol acetates with aryldiazonium salts [93]. The excitation of the porphyrin macrocycles by light irradiation initiated the catalytic cycle, generating aryl radicals from the diazonium salts, similar to findings by Gryko and co-workers. They explored both batch and continuous-flow photocatalysis

• using these systems, achieving improved yields of up to 92%. Notably, a multigram-scale experiment was successfully performed, producing 3.03 g of the desired product under continuous-flow conditions. In 2020, de Oliveira and co-workers published a review covering the field of metal-free porphyrin

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• C–H hydroxylation process by combining continuous flow chemistry and electrochemistry (Scheme 8) [16]. The surface modification of electrodes can lead to improved reactivity and selectivity. In this regard, Li and coworkers developed electron-deficient W2C nanocrystal-based electrodes to enhance the

• efficient method for C–H functionalization. The continuous flow setup allows for precise control over reaction conditions, enhanced mass transfer, and improved reaction kinetics, leading to higher efficiency and faster reaction times. In 2023, the Chiang group reported the photoelectrochemical homo-coupling

Visible-light-mediated flow protocol for Achmatowicz rearrangement

• Joachyutharayalu Oja,
• Sanjeev Kumar and
• Srihari Pabbaraja

Beilstein J. Org. Chem. 2024, 20, 2493–2499, doi:10.3762/bjoc.20.213

• reaction selectivity [25]. Continuous flow technology has emerged as an attractive solution for many of these challenges, gaining popularity for its ability to efficiently address these issues. Additionally, this platform offers the advantage of integrating multiple steps, i.e., performing multistep

• mechanism for the photochemically induced Achmatowicz rearrangement. Strategies for Achmatowicz rearrangement. Optimization of continuous flow Achmatowicz reactiona. Supporting Information Supporting Information File 133: Experimental section and NMR spectra. Supporting Information File 134: Video of the

Homogeneous continuous flow nitration of O-methylisouronium sulfate and its optimization by kinetic modeling

• Jiapeng Guo,
• Weike Su and
• An Su

Beilstein J. Org. Chem. 2024, 20, 2408–2420, doi:10.3762/bjoc.20.205

• its control difficult and risky. In this paper, a homogeneous continuous flow microreactor system was developed for the nitration of O-methylisouronium sulfate under high concentrations of mixed acids, with a homemade static mixer eliminating the mass transfer resistance. In addition, the kinetic

• 94%, initial reactant concentration of 0.5 mol/L, reaction temperature of 40 °C, molar ratio of reactants at 4.4:1, and a residence time of 12.36 minutes. Keywords: continuous flow; kinetic modeling; nitration; reaction optimization; static mixer; Introduction The demand for high-quality

• reaction process of O-methylisouronium sulfate to improve the reaction efficiency and intrinsic safety. In recent years, continuous flow microreactors have been recognized due to their excellent mass and heat transfer performance, precise control over reaction parameters, and intrinsic safety [5][6][7][8

Factors influencing the performance of organocatalysts immobilised on solid supports: A review

• Zsuzsanna Fehér,
• Dóra Richter,
• Gyula Dargó and
• József Kupai

Beilstein J. Org. Chem. 2024, 20, 2129–2142, doi:10.3762/bjoc.20.183

• the conjugate addition of propanal (22) and trans-β-nitrostyrene (11) catalysed by a simple solid-supported peptidic catalyst 24 using a continuous flow reactor. To overcome the diffusion limitations, elevated pressure was applied. Increasing the pressure from atmospheric to 60 bar resulted in a 12

• mesoporous material. Photoinduced RAFT polymerisation of n-butyl acrylate (19) catalysed by silica nanoparticle-supported eosin Y 21, which could be recycled over five reaction cycles. Pressure and temperature dependence of the 1,4-addition of propanal to trans-β-nitrostyrene under continuous flow conditions

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

• solution and in the solid state [127]. Furthermore, even sugar-functionalized pyrazoles have been accessed by this approach [128], and it was readily implemented in a continuous flow reactor [129]. Besides traditional Sonogashira catalyst systems, highly reactive and reusable immobilized Pd-complexes, such

Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications

• Matteo Gasparetto,
• Balázs Fődi and
• Gellért Sipos

Beilstein J. Org. Chem. 2024, 20, 1922–1932, doi:10.3762/bjoc.20.168

• , Alcazar et al. developed continuous flow protocols for both the generation of alkylzinc halides and for the subsequent Negishi cross-coupling reaction [40][41][42][43][44]. We successfully adapted Alcazar’s protocols for the synthesis of otherwise challenging heteroaryl–alkyl connections (see Table S1 in

• with the Negishi cross-coupling step in a continuous flow manner [41][42][43]. Continuous flow chemistry offers superior control over reaction parameters compared to traditional batch methods. This approach leads to reproducible reactions, improved safety features, and it can facilitate high-throughput

• screening and rapid optimization [46][47]. Homogenous heating and mixing in flow reactors can lead to higher reaction rates and yields. In terms of photochemistry, continuous flow setups provide enhanced light irradiation as well [48][49]. These advantages make flow chemistry a powerful tool for chemical

Synthesis of polycyclic aromatic quinones by continuous flow electrochemical oxidation: anodic methoxylation of polycyclic aromatic phenols (PAPs)

• Hiwot M. Tiruye,
• Solon Economopoulos and
• Kåre B. Jørgensen

Beilstein J. Org. Chem. 2024, 20, 1746–1757, doi:10.3762/bjoc.20.153

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• continuous flow system (Figure 26) [71]. The authors were able to demonstrate rapid benzylic fluorination of 13 substrates, requiring residence times below 30 min. The use of photoexcited aryl ketones was further expanded in 2016 by Lectka and co-workers who reported the use of 5-dibenzosuberenone as a

• fluorination in continuous flow. Photochemical phenylalanine fluorination in peptides. Decatungstate-photocatalyzed versus AIBN-initiated selective benzylic fluorination. Benzylic fluorination using organic dye Acr+-Mes and Selectfluor. Palladium-catalysed benzylic C(sp3)–H fluorination with nucleophilic

Carbonylative synthesis and functionalization of indoles

• Alex De Salvo,
• Raffaella Mancuso and
• Xiao-Feng Wu

Beilstein J. Org. Chem. 2024, 20, 973–1000, doi:10.3762/bjoc.20.87

• indolo[1,2-c]quinazolin-6(5H)-one derivatives. Finally, starting from 1,2-bis(2-nitrophenyl)ethene and 1-methoxy-2-nitro-3-(2-nitrostyryl)benzene the related indolo[3,2-b]indoles were not observed (Scheme 17). One year later, by using continuous flow technology, Gutmann, Kappe and colleagues developed a

Synthesis of 2,2-difluoro-1,3-diketone and 2,2-difluoro-1,3-ketoester derivatives using fluorine gas

• Alexander S. Hampton,
• David R. W. Hodgson,
• Graham McDougald,
• Linhua Wang and
• Graham Sandford

Beilstein J. Org. Chem. 2024, 20, 460–469, doi:10.3762/bjoc.20.41

• substrates using fluorine gas has been used successfully for the production of 5-fluorouracil (generic, anticancer) and voriconazole (V-FEND, Pfizer, antifungal) [33]. Methods have been developed for the selective monofluorination of 1,3-dicarbonyl derivatives by fluorine gas using batch and continuous flow

Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles

• Periklis X. Kolagkis,
• Eirini M. Galathri and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2024, 20, 379–426, doi:10.3762/bjoc.20.36

• development of greener synthetic technologies, like photocatalysis, organocatalysis, the use of nanocatalysts, microwave irradiation, ball milling, continuous flow, and many more. Thus, in this review, we summarize the medicinal properties of BIMs and the developed BIM synthetic protocols, utilizing the

Metal-catalyzed coupling/carbonylative cyclizations for accessing dibenzodiazepinones: an expedient route to clozapine and other drugs

• Amina Moutayakine and
• Anthony J. Burke

Beilstein J. Org. Chem. 2024, 20, 193–204, doi:10.3762/bjoc.20.19

• suitable surrogate. Not only that, the use of safer to use surrogates, is important for use in enabling technologies, like continuous flow and microwave-heated reactions. In fact, CO-free aminocarbonylation reactions are well known, and molybdenum hexacarbonyl (Mo(CO)6) is a very useful surrogate having

Optimizing reaction conditions for the light-driven hydrogen evolution in a loop photoreactor

• Pengcheng Li,
• Daniel Kowalczyk,
• Johannes Liessem,
• Mohamed M. Elnagar,
• Dariusz Mitoraj,
• Radim Beranek and
• Dirk Ziegenbalg

Beilstein J. Org. Chem. 2024, 20, 74–91, doi:10.3762/bjoc.20.9

• Supporting Information File 1, Figure S2b), while maintaining a continuous flow of N2 in the headspace through a septum. The resulting suspension exhibited a yellow/greenish color and was subsequently washed with deionized water 3–5 times, followed by drying at 70 °C overnight and grinding. The synthesized

Radical ligand transfer: a general strategy for radical functionalization

• David T. Nemoto Jr,
• Kang-Jie Bian,
• Shih-Chieh Kao and
• Julian G. West

Beilstein J. Org. Chem. 2023, 19, 1225–1233, doi:10.3762/bjoc.19.90

• . Further, we demonstrated that diazidation could be rendered catalytic using Fe(III) nitrate hydrate III as the iron source and performing the reaction under continuous flow conditions. Interestingly, this mechanism bears some similarity to Lin’s electrocatalytic diazidation, where azido radical generation

Selective and scalable oxygenation of heteroatoms using the elements of nature: air, water, and light

• Damiano Diprima,
• Hannes Gemoets,
• Stefano Bonciolini and
• Koen Van Aken

Beilstein J. Org. Chem. 2023, 19, 1146–1154, doi:10.3762/bjoc.19.82

• running the process in continuous flow [5][6][7][8]. Moreover, flow reactors that provide intense mixing can overcome the gas–liquid mass transfer limitations typical of batch reactions and improve productivity. Several studies have demonstrated the scalability and safety of such methods for the oxidation

• of water (Table 1, entries 1 and 2), the addition of oxygen (entries 1, 5, and 6) and light in the UV-A region (entries 8 and 9) turned out to be crucial (see Supporting Information File 1, Table S2). Additives With the ultimate goal in mind to develop a safe and scalable protocol in continuous flow

• ., HANU 2X 5 flow reactor) from Creaflow, as this system can easily handle demanding slurry processes under continuous-flow conditions. The reaction was carried out using an adapted setup as illustrated in Scheme 4 as triphenylphosphine is very sticky and tends to clog easily in the feeding tubes. This

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

• feedstocks, and scalability up to gram scales in continuous flow. This review provides comparisons between the two techniques (multi-photon photoredox catalysis and PEC) to help the reader to fully understand their similarities, differences and potential applications and to therefore choose which method is

• first efforts in this direction [32][33]. Finally, both techniques are amenable to large-scale synthesis and ideally integrated with state-of-the-art reactor technology platforms, such as continuous flow reactors and high throughput screening plates. Various examples of scalability will be highlighted

• indoline scaffolds (22a,b) via a radical-polar crossover mechanism (Figure 12C) [65], showcasing the power of conPET in dearomatization reactions. Finally, the synthesis of tetraphenylphosphonium chloride (20a) could be scaled up efficiently in an operationally very simple continuous-flow setup with only

Honeycomb reactor: a promising device for streamlining aerobic oxidation under continuous-flow conditions

• Masahiro Hosoya,
• Yusuke Saito and
• Yousuke Horiuchi

Beilstein J. Org. Chem. 2023, 19, 752–763, doi:10.3762/bjoc.19.55

• 10.3762/bjoc.19.55 Abstract We report on the high potential of a honeycomb reactor for the use in aerobic oxidation under continuous-flow conditions. The honeycomb reactor is made of porous material with narrow channels separated by porous walls allowing for high density accumulation in the reactor. This

• structure raised the mixing efficiency of a gas–liquid reaction system, and it effectively accelerated the aerobic oxidation of benzyl alcohols to benzaldehydes under continuous-flow conditions. This reactor is a promising device for streamlining aerobic oxidation with high process safety because it is a

• from operators or the equipment can have disastrous consequences. Because the large headspace of batch reactor aggravates these safety risks, the use of O2 in batch manufacturing is very limited [14]. Recently, continuous flow synthesis has recently been studied as a way to mitigate the safety risks

C3-Alkylation of furfural derivatives by continuous flow homogeneous catalysis

• Grédy Kiala Kinkutu,
• Catherine Louis,
• Myriam Roy,
• Juliette Blanchard and
• Julie Oble

Beilstein J. Org. Chem. 2023, 19, 582–592, doi:10.3762/bjoc.19.43

• develop a continuous flow process specifically for the C3-alkylation of furfural (Murai reaction). The transposition of a batch process to a continuous flow process is often costly in terms of time and reagents. Therefore, we chose to proceed in two steps: the reaction conditions were first optimized

• using a laboratory-built pulsed-flow system to save reagents. The optimized conditions in this pulsed-flow mode were then successfully transferred to a continuous flow reactor. In addition, the versatility of this continuous flow device allowed both steps of the reaction to be carried out, namely the

• temperature). Thus, despite the synthetic interest of the molecules that can be obtained, transfers to industry are difficult. In order to circumvent this drawback, we considered transposing these batch reactions to a flow chemistry process. In recent years, the use of continuous flow chemistry in organic

Transition-metal-catalyzed C–H bond activation as a sustainable strategy for the synthesis of fluorinated molecules: an overview

• Louis Monsigny,
• Floriane Doche and
• Tatiana Besset

Beilstein J. Org. Chem. 2023, 19, 448–473, doi:10.3762/bjoc.19.35

• . Note that in 2018, Besset and Lebel developed a more efficient process for the palladium-catalyzed trifluoromethylthiolation by C–H bond activation under continuous flow conditions [127]. I.4) Difluoromethylthiolation of aromatic and vinylic C(sp2)–H bonds (C–SCF2H and C–SCF2CO2Et bonds) More recently

Continuous flow synthesis of 6-monoamino-6-monodeoxy-β-cyclodextrin

• János Máté Orosz,
• Dóra Ujj,
• Petr Kasal,
• Gábor Benkovics and
• Erika Bálint

Beilstein J. Org. Chem. 2023, 19, 294–302, doi:10.3762/bjoc.19.25

• of Science, Charles University, 128 43 Prague 2, Czech Republic 10.3762/bjoc.19.25 Abstract The first continuous flow method was developed for the synthesis of 6-monoamino-6-monodeoxy-β-cyclodextrin starting from native β-cyclodextrin through three reaction steps, such as monotosylation, azidation

• and reduction. All reaction steps were studied separately and optimized under continuous flow conditions. After the optimization, the reaction steps were coupled in a semi-continuous flow system, since a solvent exchange had to be performed after the tosylation. However, the azidation and the

• reduction steps were compatible to be coupled in one flow system obtaining 6-monoamino-6-monodeoxy-β-cyclodextrin in a high yield. Our flow method developed is safer and faster than the batch approaches. Keywords: azidation; continuous flow; β-cyclodextrin; H-cube; 6-monoamino-6-monodeoxy-β-cyclodextrin

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