Formaldehyde surrogates in multicomponent reactions

• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Bernhard Westermann

Beilstein J. Org. Chem. 2025, 21, 564–595, doi:10.3762/bjoc.21.45

• carbon atom, due to the readiness for losing a water molecule. Formaldehyde is commonly used in its polymeric form (paraformaldehyde) or in a 37% aqueous solution (formalin). The exceptional solubility of formaldehyde in water or biobased solvents, such as ethanol and glycerol, enhances the feasibility

• [17][18]. An important drawback of this solvent is the difficulty of its removal from the reaction crude, and extractions with water are commonly employed before purification. Depending on the reaction conditions, DMSO can be transformed into different products, e.g., under redox conditions, DMSO can

• ], DMSO [64], water, and even neat conditions [62]. In some cases, the same dihalomethane can be used as both the reactant and solvent. For example, Aguilar et al., proved that when using CH2Cl2 as both a solvent and a C1 source, they could obtain propargylamines 29 with good yields from secondary amines

Binding of tryptophan and tryptophan-containing peptides in water by a glucose naphtho crown ether

• Gianpaolo Gallo and
• Bartosz Lewandowski

Beilstein J. Org. Chem. 2025, 21, 541–546, doi:10.3762/bjoc.21.42

• binding of tryptophan is therefore important for diagnostic and medicinal applications. Recently, we reported a glucose naphtho crown ether which is a chemoselective receptor for the esters of aromatic amino acids, in particular tryptophan, in water. Herein, we demonstrate that the same compound also

• binding of tryptophan in water [9]. However, the development of selective amino acid receptors in aqueous environments is challenging since it requires a combination of hydrophobic and polar interactions for binding [10][11][12]. As a result, the number of reported selective receptors for tryptophan in

• in water [21]. Crown ether 1 is particularly suited for the sensing of Trp methyl ester, which it binds with a higher affinity than the Phe and Tyr esters. Additionally, the binding of Trp-OMe results in a highly efficient fluorescence quenching of the naphthalene unit in the receptor. Herein, we

Deep-blue emitting 9,10-bis(perfluorobenzyl)anthracene

• Long K. San,
• Sebastian Balser,
• Brian J. Reeves,
• Tyler T. Clikeman,
• Yu-Sheng Chen,
• Steven H. Strauss and
• Olga V. Boltalina

Beilstein J. Org. Chem. 2025, 21, 515–525, doi:10.3762/bjoc.21.39

• , dried over 4 Å molecular sieves); quinine hemisulfate salt monohydrate (Fluka); sulfuric acid (EMD Chemicals); diethyl ether anhydrous (EMD Chemicals, ACS grade); chloroform-d (CDCl3, Cambridge Isotope Labs, 99.8%); hexafluorobenzene (C6F6, Oakwood Products); deionized distilled water (purified with a

• Barnstead NANOpure Ultrapure Water system, producing water with a final resistance of at least 18 MΩ); and silica gel (Sigma-Aldrich, 70–230 mesh, 60 Å). For HPLC separations: acetonitrile (Fisher Scientific ACS grade); toluene (Fisher Scientific, ACS grade); and heptane (Mallinckrodt Chemicals, ACS grade

• were extracted with Et2O and washed four to six times with doubly distilled water removing the aqueous layer each time. Anhydrous MgSO4 was added to the organic layer and passed through silica gel with DCM as the eluent. The organic layer was then concentrated to dryness. Yield (isolated): 9-H-10-BnF

Synthesis of N-acetyl diazocine derivatives via cross-coupling reaction

• Thomas Brandt,
• Pascal Lentes,
• Jeremy Rudtke,
• Michael Hösgen,
• Christian Näther and
• Rainer Herges

Beilstein J. Org. Chem. 2025, 21, 490–499, doi:10.3762/bjoc.21.36

• azobenzene is that the switching efficiency decreases sharply with increasing water content in the solvent. In a recently published paper, we reported that replacing one CH2 group in the bridge with NCOCH3 not only confers intrinsic water solubility, but also largely eliminates the problem of reduced

• neurotransmitters [10][11] or as switching units for potential dependent potassium channels [12]. Compared to the Z → E conversion rate of 92% (in n-hexane) of the parent diazocine the conversion in water/DMSO mixtures is decreasing with increasing water concentration (73% in water/DMSO 9:1) [8][9][10][11][12

• ]. Moreover, the parent diazocine is insoluble in water (precipitation in water/DMSO > 9:1). Substitution with polar substituents such as CH2NH2 provides water solubility, however, it does not restore the high Z → E conversion rates of the parent system in organic solvents, which is a disadvantage, since

Organocatalytic kinetic resolution of 1,5-dicarbonyl compounds through a retro-Michael reaction

• James Guevara-Pulido,
• Fernando González-Pérez,
• José M. Andrés and
• Rafael Pedrosa

Beilstein J. Org. Chem. 2025, 21, 473–482, doi:10.3762/bjoc.21.34

• a greater or lesser extent, in all the solvents tested except in water (Table 1, entry 19), where the mixture remains unchanged after 100 hours. The enantiomeric ratio of the diastereomer anti-1 depends on the solvent used, with toluene (Table 1, entry 22) providing the best results. Finally

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

• of organic solvents [34] required for light-mediated transformations including on- and in-water approaches [35][36][37], the use of supercritical CO2 as solvent [38], and the melting point depression strategy [39]. However, a more drastic option would be to remove the solvent: no solvent is the best

Beyond symmetric self-assembly and effective molarity: unlocking functional enzyme mimics with robust organic cages

• Keith G. Andrews

Beilstein J. Org. Chem. 2025, 21, 421–443, doi:10.3762/bjoc.21.30

• water (Figure 2A) [71][72][73], or by binding a hydrophobic substrate and holding it close to a functional(ized) rim (e.g., as in cyclodextrins) that performs a reaction (Figure 2B) [74][75][76][77][78][79]. These effects are driven mostly by effective concentration/molarity (i.e., proximity of reacting

• phosphodiesters by 105–107 by electrophilic activation of ester and nucleophilic activation of water or peroxide at the metal ion [101][102]. The takeaway message is that polarization is most effective when it is bifunctional. In enzymes, there is never just a nucleophile – there is always a metal, “oxyanion hole

• a size-selective space [105][126][129][130][132][134]. A key advantage is that these capsules have been made on multi-hundred-gram scales and can be recycled [132]. Additionally, control of structural or bound water by the capsule [105] and properties such as a lowered pKa inside [125] demonstrate a

Identification and removal of a cryptic impurity in pomalidomide-PEG based PROTAC

• Bingnan Wang,
• Yong Lu and
• Chuo Chen

Beilstein J. Org. Chem. 2025, 21, 407–411, doi:10.3762/bjoc.21.28

• confirmed the presence of 6 that similarly co-eluted with 3 and 7 that completely overlapped with 4 on HPLC under our standard conditions (MeCN/0.1% TFA in water, 10%→60% 0→7 min, 60%→100% 7→10 min, 100% 10→15 min) (Figure 3). The identity of these impurities was further confirmed by independent synthesis

Synthesis, structure, ionochromic and cytotoxic properties of new 2-(indolin-2-yl)-1,3-tropolones

• Yurii A. Sayapin,
• Eugeny A. Gusakov,
• Inna O. Tupaeva,
• Alexander D. Dubonosov,
• Igor V. Dorogan,
• Valery V. Tkachev,
• Anna S. Goncharova,
• Gennady V. Shilov,
• Natalia S. Kuznetsova,
• Svetlana Y. Filippova,
• Tatyana A. Krasnikova,
• Yanis A. Boumber,
• Alexey Y. Maksimov,
• Sergey M. Aldoshin and
• Vladimir I. Minkin

Beilstein J. Org. Chem. 2025, 21, 358–368, doi:10.3762/bjoc.21.26

• represent molecular switches of optical and fluorescent properties under sequential addition of CN− and Hg2+ ions and the transformation cycle presented in Scheme 3 can be repeated at least 5–6 times. The resulting compounds 7b and 8a,b have extremely low water solubility, which makes it impossible to

• prepare concentrations sufficient for studying cellular cytotoxicity. In this regard, 1,3-tropolone 7a, which has an acceptable level of solubility in water, was used for biological testing. The in vitro cytotoxic activity was investigated with A431 skin cancer and H1299 lung cancer cell lines. A standard

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

• of pyrazolo-1,2-benzothiazine derivative 5 A solution of compound 4 (269 mg, 1 mmol) in ethanol (10 mL) was refluxed with excess of hydrazine monohydrate for 24 hours. After the completion of reaction, unreacted hydrazine was removed under vacuum. Cold acidified water was poured into the residue

• . Yellow-colored precipitates of product 5 were formed which were separated via filtration followed by washing with excess of water. After drying, recrystallization was done with ethanol. Mp 265–266 °C; yield: 221 mg (88%). Synthesis of pyrazolo-1,2-benzothiazine-N-aryl/benzyl/cyclohexylacetamides 7a–h

• diluted with cold water and acidified with 5% cold HCl. The solution was allowed to stand for 15 minutes to complete precipitation. Precipitates were collected via filtration and washed with excess distilled water. The dried product was then recrystallized from absolute ethanol. Synthesis of pyrazolo-1,2

Synthesis of new condensed naphthoquinone, pyran and pyrimidine furancarboxylates

• Kirill A. Gomonov,
• Vasilii V. Pelipko,
• Igor A. Litvinov,
• Ilya A. Pilipenko,
• Anna M. Stepanova,
• Nikolai A. Lapatin,
• Ruslan I. Baichurin and
• Sergei V. Makarenko

Beilstein J. Org. Chem. 2025, 21, 340–347, doi:10.3762/bjoc.21.24

• (2c) or 4-hydroxy-2H,5H-pyrano[3,2-c][1]benzopyran-2,5-dione (2d) in yields up to 51% (Scheme 6). Furopyrimidines 7a–f were obtained by reacting bromonitroacrylates 1a,b with representatives of substituted pyrimidines 2e–g. The reactions proceed successfully by refluxing in a water–alcohol (in the

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

• isolated from a lepidopteran larva found on the leaf litter buried in the soil, on October 6, 2012. Cultivation and extraction Samsoniella aurantia was cultivated on potato dextrose agar (PDA: 200 g potato, 20 g dextrose, 15 g agar in 1 L distilled water, Difco). Mycelial plugs, each with a diameter of 7.0

• mm, were inoculated with rice in 10 × 1 L Erlenmeyer flasks, each containing 180 g of rice and 180 mL of distilled water that were foremost autoclaved, and the mixture was incubated for 16 days under static conditions at room temperature until full mycelial growth was achieved. Upon reaching optimal

• evaporation at 40 °C, forming a semi-solid residue dispersed in water. Liquid–liquid extraction against EtOAc (1:1) was conducted twice. The organic phases were combined, filtered, and evaporated under vacuum, while the aqueous phase was discarded. Isolation of compounds 1–6 The obtained organic crude extract

Effect of substitution position of aryl groups on the thermal back reactivity of aza-diarylethene photoswitches and prediction by density functional theory

• Misato Suganuma,
• Daichi Kitagawa,
• Shota Hamatani and
• Seiya Kobatake

Beilstein J. Org. Chem. 2025, 21, 242–252, doi:10.3762/bjoc.21.16

• dropwise to the solution at −78 °C, and the mixture was refluxed for 20 min. Perfluorocyclopentene (1.2 mL, 8.7 mmol) was added, and the mixture was stirred for 2 h. An adequate amount of distilled water was added to the mixture to quench the reaction. The reaction mixture was neutralized by an aqueous HCl

• mixture was refluxed for 40 min. Perfluorocyclopentene (2.2 mL, 17 mmol) was added, and the mixture was stirred for 5 h. An adequate amount of distilled water was added to the mixture to quench the reaction. The reaction mixture was neutralized by HCl aqueous solution, extracted with ether, washed with

• solution at −78 °C, and the mixture was refluxed for 40 min. 2-Methyl-3-(perfluorocyclopent-1-en-1-yl)benzofuran [68] (0.73 g, 2.3 mmol) dissolved in THF (5 mL) was added, and the mixture was stirred for 2 h. An adequate amount of distilled water was added to the mixture to quench the reaction. The

Heteroannulations of cyanoacetamide-based MCR scaffolds utilizing formamide

• Marios Zingiridis,
• Danae Papachristodoulou,
• Despoina Menegaki,
• Konstantinos G. Froudas and
• Constantinos G. Neochoritis

Beilstein J. Org. Chem. 2025, 21, 217–225, doi:10.3762/bjoc.21.13

• be established as a C1 feedstock. [25]. Its high polarity and dielectric constant (it is miscible with water) [26], with the ability to solubilize a wide range of reagents, from salts to polymers, proteins and saccharides, renders formamide an excellent C1 building block [25][27]. Thus, our target

Nickel-catalyzed cross-coupling of 2-fluorobenzofurans with arylboronic acids via aromatic C–F bond activation

• Takeshi Fujita,
• Haruna Yabuki,
• Ryutaro Morioka,
• Kohei Fuchibe and
• Junji Ichikawa

Beilstein J. Org. Chem. 2025, 21, 146–154, doi:10.3762/bjoc.21.8

• water, which effectively promoted the reaction and resulted in a 70% yield of 3bi. Furthermore, when methoxy- and ethoxy-substituted benzofurans 1c and 1d were used, the corresponding coupling products 3ca and 3da were obtained with yields of 67% and 65%, respectively. Additionally, in the coupling

Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• known processes, a particular Mannich-type reaction was realized in water in the presence of a dendritic 2,2’-bipyridine ligand 2 and Cu(OTf)2 (Scheme 2) [16]. The hydrophobic ligand surrounding the metal revealed to be essential for the organic synthesis in water, thus increasing the reaction yields

• the allyl carbenium ion VI through the loss of a molecule of water, then undergoes a Friedel–Crafts alkylation by attack of the aromatic partner. The outcome of the reaction proceeds through a Markovnikov protonation of the allylated arene VII by triflic acid, which generates the carbocation

• formation releasing Cu(OTf)2. The final bicyclic product 33 arises from isomerization and water elimination. Recently, Singh's research group developed a cascade process to access imidazo[1,2-a]pyridines-linked isoxazoles 35. Isoxazole carbaldehydes treated with 2-aminopyridines and isonitriles in the

Hot shape transformation: the role of PSar dehydration in stomatocyte morphogenesis

• Remi Peters,
• Levy A. Charleston,
• Karinan van Eck,
• Teun van Berlo and
• Daniela A. Wilson

Beilstein J. Org. Chem. 2025, 21, 47–54, doi:10.3762/bjoc.21.5

• properties are crucial, particularly its permeability. Excessive permeability allows water molecules – and potentially larger molecules – to traverse the membrane without exerting adequate force, undermining the transformation process [20][21]. Lastly, membrane stiffness plays a role; the stiffness of the

• response [23][24][25]. An excessive stiffness will eventually even impede deformation entirely [26]. This characteristic is harnessed in systems to stabilize shapes by water addition, effectively locking the membrane in a kinetically stable state [27]. In a recent study by Elafify, M. S. et al. it was

• addition water – this process was facilitated by the glass-transition temperature (Tg) of the polymer, marking the transition from a fluid to a glassy state. To replicate this methodology, it is important that the Tg of PSar-PBLG is high enough to freeze the different morphologies by water addition. The Tg

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

• -consuming. Additionally, the effect of the addition order of the reagents was evaluated, and the results are also provided in Supporting Information File 1. Furthermore, methanol, 2-propanol, and water were independently tested as reaction solvents. Solubility issues, which lead to the formation of dense

• suspensions and precipitation of the starting materials, make these solvents unsuitable for this reaction and the isolation of the products troublesome. The use of 2-propanol/water (2:1), together with the application of heat, ensures optimal solubility of the species involved. Moreover, the workup procedure

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

• photocatalytic reactions for water molecule cleavage to produce hydrogen. The mobile robot (Figure 2b) acted as a substitute of a human experimenter by executing tasks and linking eight separate experimental stations, including solid and liquid dispensing, sonication, several characterization equipments, and

• conventional photopolymerization reactions but also helps to identify structure–property relationships for copolymer libraries. We have generated a segmented flow pattern (Figure 3b) by alternating the infusion of organic components and degassed water to create nine different compositions [53]. The organic

Reactivity of hypervalent iodine(III) reagents bearing a benzylamine with sulfenate salts

• Beatriz Dedeiras,
• Catarina S. Caldeira,
• José C. Cunha,
• Clara S. B. Gomes and
• M. Manuel B. Marques

Beilstein J. Org. Chem. 2024, 20, 3281–3289, doi:10.3762/bjoc.20.272

• )benziodoxolones (BBXs) 2 with ORTEP-3 diagram of compound 2d, using 50% probability level ellipsoids. One co-crystallized water molecule was omitted for clarity. CCDC 2368436 contains the supporting crystallographic data for this paper. Scope of the different β-sulfinyl esters 4 [32][33]. Isolated yields. rt

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

• , forming a new C(sp3)–C(sp3) bond. The reaction can be performed in a phosphate-buffered saline (PBS) solution and shows post-functionalization prospects through pathways involving classical peptide chemistry. Keywords: dehydroalanine; Giese-type reaction; hydroalkylation; photocatalysis; water

• decrease in product formation (38% yield, 90% conv.), meaning BP l increases the productivity of the reaction. Having established that the reaction works in CH3CN, we evaluated its compatibility with water. To our delight, the reaction in water provided full conversion and a higher yield than the one

• observed in CH3CN (58% yield, 100% conv.; Table 1, entry 3). These conditions were further refined by adding of phosphate-buffered saline and decreasing the amount of (TMS)3SiH to 1.1 equiv, as no further increase in yield was noticed during the optimization. Similar to the reaction in deionized water, all

Intramolecular C–H arylation of pyridine derivatives with a palladium catalyst for the synthesis of multiply fused heteroaromatic compounds

• Yuki Nakanishi,
• Shoichi Sugita,
• Kentaro Okano and
• Atsunori Mori

Beilstein J. Org. Chem. 2024, 20, 3256–3262, doi:10.3762/bjoc.20.269

• ), tetrabutylammonium bromide (31.7 mg, 0.098 mmol), Pd(OAc)2 (2.2 mg, 10 mol %), and triphenylphosphine (2.8 mg, 10 mol %). The mixture was dissolved in 3.1 mL of DMA and stirring was continued at 110 °C for 24 h. Then, water (3 mL) was added after cooling to room temperature. The product was extracted with

• dichloromethane (2 mL) three times. The combined organic extracts were repeatedly washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude material, which was purified by silica gel column chromatography (hexane

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• acid as additive and a mixture of toluene and water provided the best results in terms of yield and enantioselectivity. A wide scope was explored, including electron-donating substituents and electron-withdrawing groups, as well as heterocycles, giving densely functionalized chiral azaspirocyclic

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

• GeneVac XL4 centrifugal evaporator. All solvents used for chromatography, UV, MS, and [α]D were Honeywell Burdick & Jackson or Lab-Scan HPLC grade. H2O was filtered using a Sartorius Stedium Arium Pro VF ultrapure water system. Reagents used for the total synthesis of Ianthelliformisamine D were purchased

• cultures were withdrawn, and the plates were washed twice with sterile water. Then, 50 µL of diluted RSZ solution (0.2% w/v) in LB medium was added into each well followed by incubation at 37 °C for 5 h. A microplate reader (iD5 Multi-Mode) was used to measure the fluorescence intensity (excitation 530 nm

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

• extensive scope across a range of benign solvent conditions [7][8][9][10]. In addition, the CuAAC reaction uses inexpensive Cu catalysts [11], is insensitive towards oxygen and water [12][13], and consistently delivers high yields and (where relevant) enantioselectivities [8][9][10][14][15][16][17][18][19