Oxetanes: formation, reactivity and total syntheses of natural products

• Peter Gabko,
• Martin Kalník and
• Maroš Bella

Beilstein J. Org. Chem. 2025, 21, 1324–1373, doi:10.3762/bjoc.21.101

• from esters of functionalised arylacetic acid 5 or 6 and involves two separate protocols: first, a metallacarbene, which undergoes the insertion, is generated from the corresponding diazo precursor formed either in flow via hydrazone oxidation (PS-TsNIK packed column), or in batch mode via diazo

Synthesis of β-ketophosphonates through aerobic copper(II)-mediated phosphorylation of enol acetates

• Alexander S. Budnikov,
• Igor B. Krylov,
• Fedor K. Monin,
• Valentina M. Merkulova,
• Alexey I. Ilovaisky,
• Liu Yan,
• Bing Yu and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2025, 21, 1192–1200, doi:10.3762/bjoc.21.96

• – 4500 V); mass range from m/z 50 to m/z 3000 Da; external calibration with Electrospray Calibrant Solution (Fluka). A syringe injection was used for all acetonitrile solutions (flow rate 3 μL/min). Nitrogen was applied as a dry gas; interface temperature was set at 180 °C. General reaction conditions

Recent advances in synthetic approaches for bioactive cinnamic acid derivatives

• Betty A. Kustiana,
• Galuh Widiyarti and
• Teni Ernawati

Beilstein J. Org. Chem. 2025, 21, 1031–1086, doi:10.3762/bjoc.21.85

• applications in the pharmaceutical industry. In addition, innovative synthetic methodologies, including environmentally sustainable approaches [21][22][23], advanced catalytic systems [24][25][26], photocatalysis [27][28][29], and cutting-edge technologies, such as flow chemistry [30][31], have contributed

• the electrophilic triazinedione, releasing DMAP to give ester 15 which reacts with DMAP to afford the active N-acylpyridinium species 16. In addition, N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC·HCl), a common coupling reagent, has been applied for a continuous flow

• scaled up to a gram scale. Uozumi and co-workers (2019) reported a carbonylation under aqueous flow conditions using alkenyl halide 240 to prepare cinnamic acid (7) catalyzed by an amphiphilic polystyrene-poly(ethylene glycol) resin-supported Pd-diphenylphosphine catalyst (cat 6) (Scheme 65A) [31]. Also

Recent advances in the electrochemical synthesis of organophosphorus compounds

• Babak Kaboudin,
• Milad Behroozi,
• Sepideh Sadighi and
• Fatemeh Asgharzadeh

Beilstein J. Org. Chem. 2025, 21, 770–797, doi:10.3762/bjoc.21.61

• recent years on developing new methods for synthesizing organophosphorus compounds [22][23][24][25][26][27][28][29][30][31][32][33][34][35]. Developing sustainable and green methods for synthesizing organophosphorus materials is a growing field. Methods based on photocatalysis [36], flow-based

• recent years. Recently, an electrochemical reaction of 2-isocyanobiaryls with diphenylphosphine oxides has been reported by Li et al. [45] using a Mn catalytic system with C(anode)/Pt(cathode) in an undivided cell. Different products were obtained with up to 85% yield in a constant flow for three hours

• the gram-scale preparation of some samples. An electrochemical flow system was used in this method, in which carbon and platinum electrodes were used as the anode and cathode, respectively, at a constant current of 55 mA (Scheme 8). Due to the steric hindrance caused by the tert-butyl group, the

Development and mechanistic studies of calcium–BINOL phosphate-catalyzed hydrocyanation of hydrazones

• Carola Tortora,
• Christian A. Fischer,
• Sascha Kohlbauer,
• Alexandru Zamfir,
• Gerd M. Ballmann,
• Jürgen Pahl,
• Sjoerd Harder and
• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2025, 21, 755–765, doi:10.3762/bjoc.21.59

• -state structure, two bonds (Ca–O and Si–C) are broken, while a Si–O bond is simultaneously formed, in a concerted step implying a cyclic flow of six electrons in a five-membered ring. The isocyanide Ca–N–C bond angle in TS 11-12 lies between that of 7 and 9. While the replacement step is slow, and hence

Synthesis of HBC fluorophores with an electrophilic handle for covalent attachment to Pepper RNA

• Raphael Bereiter and
• Ronald Micura

Beilstein J. Org. Chem. 2025, 21, 727–735, doi:10.3762/bjoc.21.56

• analyzed by AE chromatography (Dionex DNAPac PA-100 column; 4 mm × 250 mm) at 80 °C with a flow rate of 1.0 mL/min. A gradient of 25–37.5% B in A in 25.0 minutes was used; Eluent A: 25 mM Tris∙HCl, 10 mM NaClO4, 20% acetonitrile, pH 8.0; eluent B: 25 mM Tris∙HCl, 600 mM NaClO4, 20% acetonitrile, pH 8.0

Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

• introduction of –CHF– or –CF2– as a replacement for the ring oxygen, or for one (or more) of the –CH(OH)– groups, or for the anomeric oxygen. The various conformational outcomes that flow from making such modifications are discussed below. It should be noted that introducing fluorine into sugars has many other

• negative fluorine atom and the positively charged C=O+ moiety, and σC–H → σ*C–F hyperconjugation. The fluorine atom thus shields the top face of the oxocarbenium ion, and this has flow-on effects on the rate and stereoselectivity of subsequent glycosylation reactions [139]. Another important rotatable bond

Asymmetric synthesis of fluorinated derivatives of aromatic and γ-branched amino acids via a chiral Ni(II) complex

• Maurizio Iannuzzi,
• Thomas Hohmann,
• Michael Dyrks,
• Kilian Haoues,
• Katarzyna Salamon-Krokosz and
• Beate Koksch

Beilstein J. Org. Chem. 2025, 21, 659–669, doi:10.3762/bjoc.21.52

• . The prepared samples were injected into the spray chamber using a syringe pump with flow rates of 10 to 40 μL/min. The desolvation gas was adjusted to 15 psi. Other parameters were optimized for maximal abundance of [M + H]+, [M + Na]+, or [M + K]+. High-resolution electron ionization mass spectra

• ) was used. MeCN/MeOH/H2O mixture with 50 mM formic acid and 25 mM diethylamine was used as eluent. A flow rate of 0.5 mL/min was applied and the detection of the respective compounds occurred at 280 nm. Data analysis was carried out with the EZChrom ELITE software (version 3.3.2 SP2, Agilent). Ni(II

Semisynthetic derivatives of massarilactone D with cytotoxic and nematicidal activities

• Rémy B. Teponno,
• Sara R. Noumeur and
• Marc Stadler

Beilstein J. Org. Chem. 2025, 21, 607–615, doi:10.3762/bjoc.21.48

• ), solvent A: H2O + 0.1% formic acid; solvent B: acetonitrile (ACN) + 0.1% formic acid, gradient: 5% B for 0.5 min, increasing to 100% B in 20 min, maintaining isocratic conditions at 100% B for 10 min, flow = 0.6 mL/min, UV–vis detection 190–600 nm]. Preparative HPLC was achieved at room temperature on an

• Agilent 1100 series preparative HPLC system [ChemStation software (Rev. B.04.03 SP1); binary pump system; column: Kinetex 5u RP C18, dimensions 250 × 21.20 mm; mobile phase: ACN + 0.05% trifluoroacetic acid (TFA) and water + 0.05% TFA; flow rate: 20 mL/min; diode array UV detector; 226 fraction collector

• software (Rev. B.04.03 SP1); binary pump system; column: Kinetex 5u RP C18, dimensions 250 × 21.20 mm; mobile phase: ACN + 0.05% trifluoroacetic acid (TFA) and water + 0.05% TFA; flow rate 20 mL/min; diode array UV detector; 226 fraction collector. A gradient from 47 to 72% solvent B in 50 min was used

Photomechanochemistry: harnessing mechanical forces to enhance photochemical reactions

• Francesco Mele,
• Ana M. Constantin,
• Andrea Porcheddu,
• Raimondo Maggi,
• Giovanni Maestri,
• Nicola Della Ca’ and
• Luca Capaldo

Beilstein J. Org. Chem. 2025, 21, 458–472, doi:10.3762/bjoc.21.33

• hydrogen-atom transfer or solvolysis are often observed. A technological solution to cope with the Beer–Lambert law was offered by flow chemistry [19][20][21] by employing microreactors with reduced optical paths to enhance irradiation efficiency [22][23][24]. Photon-limited reactions, whose efficiency is

• primarily constrained by the availability of photons in the reaction mixture, particularly benefit from this approach. Paradoxically, flow chemistry is a convenient technology to increase the productivity of photochemical reactions via numbering-up and sizing-up approaches [25], but it is highly dependent

• on solvents. In fact, high concentrations of reagents or products can lead to precipitation, causing undesired clogging of the reactor and potentially disastrous consequences for the intended transformation. It is important to mention that specific solutions for handling slurries in flow have been

Synthesis, characterization, antimicrobial, cytotoxic and carbonic anhydrase inhibition activities of multifunctional pyrazolo-1,2-benzothiazine acetamides

• Ayesha Saeed,
• Shahana Ehsan,
• Muhammad Zia-ur-Rehman,
• Erin M. Marshall,
• Sandra Loesgen,
• Abdus Saleem,
• Simone Giovannuzzi and
• Claudiu T. Supuran

Beilstein J. Org. Chem. 2025, 21, 348–357, doi:10.3762/bjoc.21.25

• (Figure S44 in Supporting Information File 1). In vitro carbonic anhydrase inhibition In vitro assessment of all targeted pyrazolobenzothiazine scaffolds for human carbonic anhydrase (hCA) inhibition was performed adopting a stopped-flow CO2 hydration method. The enzyme inhibition assays were carried out

• -diphenyltetrazolium bromide]. Control metabolic activity shown by cells treated with 0.1% DMSO was set to 100% cell growth. CA inhibition assays The inhibition potential of the synthesized compound 7a–h against different hCAs (I, II, IX, XII) was analyzed by adopting a stopped-flow CO2 hydration method described by

• /benzyl/cyclohexyl groups. Experimental data of microbroth dilution assays against different strains of S. aureus.a Experimental data of human carbonic anhydrase (hCAs) inhibition assays adopting a stopped-flow CO2 hydration method. Supporting Information Supporting Information File 6: Experimental

Antibiofilm and cytotoxic metabolites from the entomopathogenic fungus Samsoniella aurantia

• Rita Toshe,
• Syeda J. Khalid,
• Blondelle Matio Kemkuignou,
• Esteban Charria-Girón,
• Paul Eckhardt,
• Birthe Sandargo,
• Kunlapat Nuchthien,
• J. Jennifer Luangsa-ard,
• Till Opatz,
• Hedda Schrey,
• Sherif S. Ebada and
• Marc Stadler

Beilstein J. Org. Chem. 2025, 21, 327–339, doi:10.3762/bjoc.21.23

• ) were acquired using a Thermo-Fischer Scientific UltiMate 3000 Series UPLC (Waltham, MA, USA) equipped with a C18 column (Acquity UPLC BEH 50 × 2.1 mm, 1.7 µm; Waters, Milford, MA, USA) and an amaZon speed ESI-Ion trap-MS (Bruker) with a sample injection volume of 2 µL and a flow rate of 0.6 mL/min. A

• phase consisted of deionized water (H2O) + 0.1% formic acid as solvent A and MeCN + 0.1% formic acid as solvent B. The flow rate was set at 30 mL/min for fractions 3, 4, and 8, and 20 mL/min for fraction 6. The collected fraction volume for each run was 15 mL. In the purification of fraction 3 (1,315 mg

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

• yield gain of 27.5% at the same reaction scale. T. Rovis et al. emphasize this result has profound implications for industrial applications. The ability of red light to penetrate deeply and to maintain high efficiency without requiring specialized flow reactors or high-powered light sources makes the

• deeper penetration through the reaction media, making the method highly scalable. In a batch reaction, the authors have successfully scaled up the synthesis by two orders of magnitude, achieving comparable yields without the need for complex flow reactors. The successful implementation of osmium

• 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

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

Facile one-pot reduction of β-nitrostyrenes to phenethylamines using sodium borohydride and copper(II) chloride

• Laura D’Andrea and
• Simon Jademyr

Beilstein J. Org. Chem. 2025, 21, 39–46, doi:10.3762/bjoc.21.4

• mm, 1.7 µm) operated at 40 °C, using a linear gradient of the binary solvent system of buffer A (Milli-Q H2O/MeCN/formic acid, 95:5:0.1 v/v) to buffer B (MeCN/formic acid, 100:0.1 v/v) from 0 to 100% B in 3.5 min, then 1 min at 100% B, flow rate: 0.8 mL/min. Data acquisition was controlled by

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

• . [6], and Sagmeister et al. [7]. The first two offer valuable perspectives on chemical reaction optimization, particularly focusing on process scale-up, while the latter discusses the potential of flow platforms for self-optimization reactions. Additionally, we refer the readers to the following

• synthesis. HTE using batch modules Batch reactions occur without flow of the reagents/products into or out of the reaction vessel until a target conversion has been achieved. HTE batch platforms leverage on parallelization of experiments to perform several reactions under different conditions simultaneously

• perform most tasks in chemical and material synthesis, the hardware currently cannot perform product purification and multistep synthesis continuously. HTE using flow platforms Flow reactions are characterized by a constant flow of reagents and products into and out of the reaction vessel. A flow platform

Giese-type alkylation of dehydroalanine derivatives via silane-mediated alkyl bromide activation

• Perry van der Heide,
• Michele Retini,
• Fabiola Fanini,
• Giovanni Piersanti,
• Francesco Secci,
• Daniele Mazzarella,
• Timothy Noël and
• Alberto Luridiana

Beilstein J. Org. Chem. 2024, 20, 3274–3280, doi:10.3762/bjoc.20.271

• Perry van der Heide Michele Retini Fabiola Fanini Giovanni Piersanti Francesco Secci Daniele Mazzarella Timothy Noel Alberto Luridiana Department of Chemical and Geological Sciences, University of Cagliari, S.S. 554, bivio per Sestu, 09042 Monserrato (CA), Italy Flow Chemistry Group, Van ’t Hoff

• (N); state-of-the-art: (c) silane-mediated alkylation initiated by a photocatalyst, (d) silane-mediated alkylation initiated by photolysis of alkyl iodides, (e) silane-mediated alkylation initiated by photolysis of alkyl bromides in flow; this work: silane-mediated alkylation of Dha derivatives

Ceratinadin G, a new psammaplysin derivative possessing a cyano group from a sponge of the genus Pseudoceratina

• Shin-ichiro Kurimoto,
• Kouta Inoue,
• Taito Ohno and
• Takaaki Kubota

Beilstein J. Org. Chem. 2024, 20, 3215–3220, doi:10.3762/bjoc.20.267

• MeCN/H2O/TFA 45:55:0.1; flow rate 2.5 mL/min; UV detection at 254 nm), yielding psammaplysin F (2, tR 14 min, 6.9 mg, 0.0056% wet weight) and ceratinadin G (1, tR 56 min, 0.4 mg, 0.00032% wet weight). Ceratinadin G (1): colorless amorphous solid; [α]D27 −71.0 (c 0.02, MeOH); UV (MeOH) λmax, nm: 207 (ε

Discovery of ianthelliformisamines D–G from the sponge Suberea ianthelliformis and the total synthesis of ianthelliformisamine D

• Sasha Hayes,
• Yaoying Lu,
• Bernd H. A. Rehm and
• Rohan A. Davis

Beilstein J. Org. Chem. 2024, 20, 3205–3214, doi:10.3762/bjoc.20.266

• run over 50 min at a flow rate of 9 mL/min; 60 fractions (60 × 1 min) were collected and resulted in the purification of the known sterol, aplysterol (8, 0.9 mg, tR 12–13 min, 0.009% dry wt). The extraction and isolation process described above was repeated twice more (identical scale) to obtain

Germanyl triazoles as a platform for CuAAC diversification and chemoselective orthogonal cross-coupling

• John M. Halford-McGuff,
• Thomas M. Richardson,
• Aidan P. McKay,
• Frederik Peschke,
• Glenn A. Burley and
• Allan J. B. Watson

Beilstein J. Org. Chem. 2024, 20, 3198–3204, doi:10.3762/bjoc.20.265

• azide precursors and the formation of a single 1,4-disubstituted triazole product, the copper-catalysed azide–alkyne cycloaddition (CuAAC) remains the archetypal click reaction (Scheme 1) [5]. The reaction has shown applicability on small and large scale, as well as under flow conditions [6], and

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

Advances in radical peroxidation with hydroperoxides

• Oleg V. Bityukov,
• Pavel Yu. Serdyuchenko,
• Andrey S. Kirillov,
• Gennady I. Nikishin,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2024, 20, 2959–3006, doi:10.3762/bjoc.20.249

• ) [51]. The corresponding peroxides 30 are enough stable under the reaction conditions and were isolated in high yields (Scheme 12). Flow-modification of the 2-oxoindole peroxidation method using nanoparticles of iron oxide as the catalyst was proposed [52]. The summarized proposed reaction pathway is

Applications of microscopy and small angle scattering techniques for the characterisation of supramolecular gels

• Connor R. M. MacDonald and
• Emily R. Draper

Beilstein J. Org. Chem. 2024, 20, 2608–2634, doi:10.3762/bjoc.20.220

• , and flow [62]. Sample environments can also be as simple as a capillary at ambient conditions. Without a need for the sample environment to be under vacuum, as is required for some microscopy techniques as previously discussed, SAS allows for volatile solvent systems to be characterised. In addition

• rheology alone cannot provide. By using rheo-SANS, the structural order of the micelle solutions could be determined under flow. Worm-like micelles can align under shear, however, it was shown that under sufficiently high strain a plateau in viscosity is reached before again undergoing shear-thinning under

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

• gaining increasing interest in both academia and industry due to its numerous advantages and potential applications [1][2]. Electrochemical methods can reduce costs and waste generation by eliminating the need for chemical oxidants or reductants, and they can be safely and easily scaled up in flow

• of ¹³¹I-labeled compounds. For example, the late-stage iodoamination of cytisine, amoxapine, and fluoxetine hydrochloride was achieved with yields of 65%, 87%, and 73%, respectively. Additionally, this transformation was successful for gram-scale synthesis via batch and flow chemistry, indicating

• 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

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

• and development of a visible light-assisted modular photo-flow reactor with a seamlessly integrated post-synthetic work-up procedure enabling the efficient synthesis of dihydropyranones from furfuryl alcohols. The reaction uses sun light as green energy source, and the novel photo-flow reactor

• platform developed with an integrated system enabling a downstream process in a time and labor-efficient manner which facilitates the Achmatowicz rearrangement, resulting in a fast (10 min) formation of the dihydropyranone products. Keywords: Achmatowicz reaction; flow chemistry; furfuryl alcohols

• et al. [22] have demonstrated a combined use of flow and batch processes involving an electrochemical flow cell for the oxidation of furfuryl alcohols and subsequently utilizing the crude electrolysis mixture for hydrolysis in a traditional batch process to get the rearranged Achmatowicz product. As