Design, synthesis and biological evaluation of 2,5-diaryloxazolo[4,5-d]pyrimidin-7-ylamines as selective cytotoxic agents against HeLa cells

• Maryna V. Kachaeva,
• Agnieszka B. Olejniczak,
• Marta Denel-Bobrowska,
• Victor V. Zhirnov,
• Yevheniia S. Velihina,
• Stepan G. Pilyo and
• Volodymyr S. Brovarets

Beilstein J. Org. Chem. 2026, 22, 390–398, doi:10.3762/bjoc.22.27

• addition of a 4-chlorophenyl group instead of the methyl group as a functional motif at position 7 (4) sharply reduced the cytotoxicity of compound 1. The substitution of piperidine by morpholine in this motif in compound 4 resulted in a 2-fold increase in the activity of the obtained derivative 5. However

• results for a particular parameter obtained from different platforms increases the reliability of the prediction [20]. In addition, during the development of chemotherapeutics, oral bioavailability is desirable but not critical, given the preference for the parenteral route of administration. Due to the

Dialkylaminoalkylation of β-ketosulfones via ring-opening of 3-sulfonylpyrrolidines

• Evgeny M. Buev,
• Alexander V. Pavlushin,
• Vladimir S. Moshkin and
• Vyacheslav Y. Sosnovskikh

Beilstein J. Org. Chem. 2026, 22, 383–389, doi:10.3762/bjoc.22.26

• of the quaternary ammonium salt in the presence of a O-, S- or N-nucleophile with cesium carbonate leads to a retro-Claisen reaction, ring-opening and Michael addition. The resulting novel 4-Nu-3-sulfonylbutan-1-amines are isolated in moderate to excellent overall yields. The reduction of the

• the fast increase of the molecular complexity, remains significant. Unlike the classical aminoethylation of nucleophilic compounds [28][29], Batey et al. recently developed a two-step approach consisted in addition of terminal ynimides I to various electrophiles with subsequent reduction of the C≡C

• radical addition (Figure 2c) [31]. In the continuation of our work on application of pyrrolidines as sacrificial framework for the alkylaminomethylation of enones [32][33] we turned our attention to active methylene compounds IV as precursors of pyrrolidines. Preliminary experiments demonstrated that the

Electrosynthetic access to unsymmetrical oxaza[8]helicenes with high chiral stability and strong circularly polarized luminescence (CPL)

• Tin Zar Aye,
• Rubal Sharma,
• Muthu Karuppasamy,
• Daiya Suzuki,
• Haruka Nakajima,
• Yoshitane Imai,
• Mitsuhiro Arisawa,
• Mohamed S. H. Salem and
• Shinobu Takizawa

Beilstein J. Org. Chem. 2026, 22, 372–382, doi:10.3762/bjoc.22.25

• -bromophenanthrene (1) via Buchwald–Hartwig amination with p-toluidine under Pd catalysis [55] – was subjected to phosphoric acid-mediated annulation with p-benzoquinone to give the hydroxycarbazole derivative 3 through a tandem Michael addition/ring-closure sequence. After rapid optimization of key parameters (see

Recent advances in the cleavage of non-activated amides

• Eun-Sol Choi and
• Hyo-Jun Lee

Beilstein J. Org. Chem. 2026, 22, 352–369, doi:10.3762/bjoc.22.23

• ]. Such activation has enabled a wide array of transformations, including metal-catalyzed cross-couplings via oxidative addition into the amide C–N bond (Scheme 1c) [32][33][34][35][36], and transition-metal-free acyl substitutions facilitated by improved leaving-group ability [37][38][39][40]. Although

• 1), addition of water affords adduct M, which subsequently converts to the ester via deprotonation. In dry solvents (path 2), nucleophilic attack by the departing OSO₂F− anion on L produces intermediate N, containing an S–O bond that is ultimately cleaved under basic conditions to yield the ester

• 2.2 equivalents of 2-bromopyridine as a base, pyrrolidine-derived amides 38 were effectively activated. Subsequent addition of NFSI as the electrophilic fluorinating reagent, along with alcohols as the nucleophile, afforded the corresponding esters 39–43 in moderate yields. Mechanistically, the

Synthesis of tricyclic fused pyrrolidine nitroxides from 2-alkynylpyrrolidine-1-oxyls

• Mark M. Gulman,
• Yuliya F. Polienko,
• Sofia Yu. Trakhininа,
• Yuri V. Gatilov,
• Tatyana V. Rybalova,
• Sergey A. Dobrynin and
• Igor A. Kirilyuk

Beilstein J. Org. Chem. 2026, 22, 344–351, doi:10.3762/bjoc.22.22

• -alkynyl-substituted pyrrolidine nitroxides was studied. These nitroxides have been prepared via intramolecular Huisgen cycloaddition or intramolecular alkylation in 2-pyrazolyl derivatives prepared by Michael addition–cyclocondensation of the corresponding alkynones with hydrazine. The reduction kinetics

• Huisgen cycloaddition or via one-pot Michael addition–cyclocondensation reaction with hydrazine with subsequent intramolecular alkylation of the resulting pyrazoles. Results and Discussion Synthesis We have earlier reported on the synthesis of 2-alkynylpyrrolidine-1-oxyls 2a–c via addition of the

• of reduction is an important factor for application of a nitroxide as an EPR spin probe or as a component of a MRI contrast agent. The bimolecular rate constants of reduction of radicals 2a–f, 4a–f and 9c with ascorbate were measured with addition of the glutathione system to suppress reverse

Ring contraction and ring expansion reactions in terpenoid biosynthesis and their application to total synthesis

• Nicolas Kratena,
• Nicolas Heinzig and
• Peter Gärtner

Beilstein J. Org. Chem. 2026, 22, 289–343, doi:10.3762/bjoc.22.21

• addition towards the highly electrophilic α-diketone moiety. With this, the bicyclic lathyrane skeleton of jolkinol C (45) is assembled selectively from casbene. The large family of indole meroterpenoids [94][95][96][97][98] also contains an interesting, enzyme-mediated ring-expansion reaction. According

• ) and B (78) the tricyclic precursor 79 was invoked (see Scheme 22B) [129]. This compound could undergo oxidation at the alkene (and C-1) to give intermediate 80, which after oxidative cleavage affords the enolate of diketone 82 which can undergo transannular aldol addition to give either product 77 or

• enables selective C-4 to C-14 ketone aldolisation furnishing pepluanol D (87). The same authors also proposed a putative biosynthetic origin for the intriguing 5/4/7/3-ring system of pepluacetal (89) from pepluanol A (88) by olefin isomerisation (88a to 88b) and 1,6-conjugate addition to build up the new

Arene activation via π-bond localization: concepts and opportunities

• Paul Meiners,
• Julian J. Melder and
• Tobias Morack

Beilstein J. Org. Chem. 2026, 22, 257–273, doi:10.3762/bjoc.22.19

• following sections therefore focus on the selective disruption of aromaticity through the formation of transition metal–arene π-complexes. Transient and reversible coordination of transition metals to aromatic π-systems is a key feature of many catalytic transformations, with the oxidative addition of

• palladium to aryl halides serving as a prominent example [41]. In addition to such fleeting intermediates, recent decades have seen the emergence of numerous well-defined metal–arene complexes, sufficiently stable to enable systematic exploration of their rich and versatile organic chemistry. η2

• ; Figure 4B) [44][45][46]. Collectively, these changes alter the innate reactivity of the arene, steering η2-coordinated systems toward electrophilic addition, cycloaddition, and hydrogenation processes. While many transition metals can engage aromatic rings through η2-coordination, only a handful have

A mild and atom-efficient four-component cascade strategy for the construction of biologically relevant 4-hydroxyquinolin-2(1H)-one derivatives

• Dmitrii A. Grishin,
• Kseniia I. Sharkovskaia,
• Ilya G. Kolmakov,
• Daria A. Ipatova,
• Rostislav A. Petrov,
• Nikolai D. Dagaev,
• Dmitry A. Skvortsov,
• Maria G. Khrenova,
• Valeriy V. Andreychev,
• Sergei A. Evteev,
• Yan A. Ivanenkov,
• Roman L. Antipin,
• Olga А. Dontsova and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2026, 22, 244–256, doi:10.3762/bjoc.22.18

• acids followed by sequential Michael-type addition and subsequent cascade transformations. This versatile one-pot protocol delivers structurally diverse open-chain 3-arylpropanoate esters in moderate to good yields (46–69%), while cyclic pyranoquinolinones are formed under kinetically controlled

• direct access to scarcely explored open-chain quinolinone esters, expanding the medicinal chemistry toolbox with promising scaffolds for drug discovery. Keywords: antibacterial activity; 4-hydroxyquinolin-2(1H)-one; ʟ-proline catalysis; Meldrum’s acid; Michael addition; multicomponent reaction

• developing a synthetic strategy for esters of 3-(4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-3-arylpropanoic acids, we initially performed a retrosynthetic analysis of the target chemotype (Scheme 2) and proposed two plausible synthetic routes, identifying a Michael 1,4-addition as the key step. The first

Conformational analysis of difluoromethylornithine: factors influencing its gas-phase and bioactive conformations

• Matheus P. Freitas

Beilstein J. Org. Chem. 2026, 22, 237–243, doi:10.3762/bjoc.22.17

• difluoromethyl moiety is significantly less repulsive in structure 4. In addition, the zigzag conformation of the N-alkyl chain reduces σCN/σCC repulsions. Structure 5 (type II) displays a comparatively low steric penalty (294.0 kcal mol−1), much smaller than those of structures 1–3. This reduction arises in

Configuration–packing synergy enabling integrated crystalline-state RTP and amorphous-state TADF

• Ruiyan Wang and
• Yunan Wu

Beilstein J. Org. Chem. 2026, 22, 224–236, doi:10.3762/bjoc.22.16

• Figure 5b. This indicates that the specific molecular arrangement necessary for RTP was disrupted upon melting and subsequent rapid cooling, suggesting that the ordered structure in the solid phase is essential for the RTP phenomenon. In addition to the optical measurements, powder X-ray diffraction

Synthesis of diaryl phosphates using phytic acid as a phosphorus source

• Kazuya Asao,
• Seika Matsumoto,
• Haruka Mori,
• Riku Yoshimura,
• Takeshi Sasaki,
• Naoya Hirata,
• Yasuyuki Hayakawa and
• Shin-ichi Kawaguchi

Beilstein J. Org. Chem. 2026, 22, 213–223, doi:10.3762/bjoc.22.15

• )phosphide anion [P(SiCl3)2]−, can be converted into a variety of phosphorus compounds, including P(III) species, demonstrating the potential to reduce reliance on white phosphorus (Figure 2B) [42][43]. In addition, Weigand’s group reported a method using Tf2O and pyridine to convert P(V) compounds such as

• 2c in comparison to the other substrates due to steric hindrance. In addition, when 1i and 1j were used, the corresponding phosphate ester 2i was not obtained at all, and 2j was formed only in a low yield. It is well known that phenols containing strong electron-withdrawing groups can be good leaving

• different mechanisms. In addition, the DPpyP 31P NMR peak increases and decreases in conjunction with the decrease of the MPP peak and increase of the DPP peak, suggesting that DPpyP acts as an intermediate in the DPP formation process. When alcohol 1c was used (Figure 3), the reaction stopped mainly at the

Screwing the helical chirality through terminal peri-functionalization

• Devesh Chandra,
• Sachin and
• Upendra Sharma

Beilstein J. Org. Chem. 2026, 22, 205–212, doi:10.3762/bjoc.22.14

• method for the generation of helical chirality primarily involves cycloaddition and central/axial to helical chirality transfer reactions [31] (Figure 1A and B). In addition to this, a parallel strategy also offers a promising approach to achieving configurationally stable helicenes via terminal peri

• catalysts [33]. A domino reaction was developed, beginning with a PPS L2-catalyzed Michael addition of phosphine oxides 7 to nitro-substituted oxa[5]helicenes 6, followed by a copper-promoted aromatization. This sequence efficiently produced phosphorus-containing oxa[5]helicene derivatives 8 in high yields

• and with excellent enantioselectivities. The catalytic system operated under mild conditions within a practical timeframe and demonstrated broad substrate tolerance, providing a range of chiral helicenes. Notably, unsymmetrical phosphine oxides also underwent smooth Michael addition, with excellent

Base-promoted deacylation of 2-acetyl-2,5-dihydrothiophenes and their oxygen-mediated hydroxylation

• Vladimir G. Ilkin,
• Margarita Likhacheva,
• Igor V. Trushkov,
• Tetyana V. Beryozkina,
• Vera S. Berseneva,
• Vladimir T. Abaev,
• Wim Dehaen and
• Vasiliy A. Bakulev

Beilstein J. Org. Chem. 2026, 22, 192–204, doi:10.3762/bjoc.22.13

• phenols [25]. Hocking has described the oxidation of o-hydroxyacetophenone and some benzophenones with an aqueous alkaline hydrogen peroxide solution [26]. The key steps of oxidation of ketones into phenols include: a) nucleophilic addition of the hydroperoxide anion to the carbonyl carbon; b) [1,2]-aryl

• amide group plays an important role in these transformations. In addition, analysis of the reaction mixture obtained in ethanolic solution was performed after evaporation of the ethanol. HRMS analysis showed the presence of two peaks with m/z values 400.1704 (retention time 7.952‒7.963) and 400.1700

Streptoquinolines A and B, new antibacterial meroterpenoids produced by Streptomyces sp. TMPU-A0679

• Akiho Yagi,
• Hitomi Tomura,
• Ami Konno and
• Ryuji Uchida

Beilstein J. Org. Chem. 2026, 22, 185–191, doi:10.3762/bjoc.22.12

• acetone; therefore, they may be artifacts that formed via the nucleophilic addition of acetone to a ketone-bearing precursor during the extraction process. Despite various modifications to fermentation conditions, it was not possible to detect or isolate the presumed natural precursor. We are currently

• nm (approximately 1.0 × 108 CFU/mL). The suspensions were then further diluted 3,000-fold with fresh broth. Aliquots of 95 µL of the diluted suspension were dispensed into the wells of a 96-well microplate, followed by the addition of 5 µL of test samples dissolved in methanol. The microplate was

Improved synthesis and physicochemical characterization of the selective serotonin 2A receptor agonist 25CN-NBOH

• Adrian G. Rossebø,
• Hannah G. Kolberg,
• Anders E. Tønder,
• Louise Kjaerulff,
• Poul Erik Hansen,
• Karla A. Frydenvang,
• Jesper Østergaard and
• Jesper L. Kristensen

Beilstein J. Org. Chem. 2026, 22, 175–184, doi:10.3762/bjoc.22.11

• modest 65% [12]. In the present work, we found that simply adding 4 Å molecular sieves powder during the formation of the intermediate imine gave a much cleaner reaction and increased the yield of 1·HCl from 2C-CN·HCl to 74%. We suggest that the addition of the molecular sieves facilitates the formation

• minutes. Finally, quenching was done by careful addition of aqueous citric acid (12.5 mL, 1 M) while cooling in an ice bath. The resulting mixture was filtered through a pad of Celite and diluted with dichloromethane (75 mL) and water (75 mL), and the aqueous phase was adjusted to pH 8–9 using saturated

• . Crystallization was done by dissolving the compound in boiling EtOH (32 mL), slow cooling to room temperature, and ensuring complete precipitation by addition of the same volume of Et2O and cooling to 0 °C, after which the solids were collected by vacuum filtration. Drying under high vacuum provided the product 1

A new synthesis of Tyrian purple (6,6’-dibromoindigo) and its corresponding sulfonate salts

• Holly Helmers,
• Mark Horton,
• Julie Concepcion,
• Jeffrey Bjorklund and
• Nicholas C. Boaz

Beilstein J. Org. Chem. 2026, 22, 167–174, doi:10.3762/bjoc.22.10

• Scheme 5A, dimethyl sulfoxide (DMSO) did not react with the benzyl bromide and instead only returned the starting material. The addition of 1.2 equivalents of silver nitrate promoted the substitution of the benzyl bromide with DMSO to yield an alkoxysulfonium ion 8 [22]. Following substitution, the

• addition of 1.2 equivalents of triethylamine mediated the formation of 4 in moderate yield, as shown in Scheme 5B (57% isolated, 67% based on NMR). The crude product was sufficiently pure (84 wt % by quantitative NMR) to carry on without purification, but further purification was possible by

Circumventing Mukaiyama oxidation: selective S–O bond formation via sulfenamide–alcohol coupling

• Guoling Huang,
• Huarui Zhu,
• Shuting Zhou,
• Wanlin Zheng,
• Fangpeng Liang,
• Zhibo Zhao,
• Yifei Chen and
• Xunbo Lu

Beilstein J. Org. Chem. 2026, 22, 158–166, doi:10.3762/bjoc.22.9

• group compatibility. The reaction was further applicable to naphthyl sulfenamides, as demonstrated by the successful conversion of a 2-naphthyl derivative to 3p in 70% yield. In addition, alkyl sulfenamides derived from thiols, including cyclohexyl (3q) and linear alkyl chains (3r), gave the desired

• and 2-phenylethanol, were well tolerated. These substrates afforded the corresponding sulfinimidate esters 3m’–q’ in 70–90% yields. In addition to linear alcohols, cycloalkyl-substituted primary alcohols such as cyclobutylmethanol and cyclopentylmethanol were also examined. These small-ring systems

• , the sulfenamide-based oxidative coupling proceeded smoothly, delivering sulfilimidate ester 4 in 53% yield. In addition, the transformation was applied to a chiral secondary alcohol, ʟ-menthol, to generate the sulfilimidate ester 5 in 67% yield. A diastereomeric analysis revealed a modest dr of 1.6:1

Asymmetric Mannich reaction of aromatic imines with malonates in the presence of multifunctional catalysts

• Kadri Kriis,
• Harry Martõnov,
• Annette Miller,
• Mia Peterson,
• Ivar Järving and
• Tõnis Kanger

Beilstein J. Org. Chem. 2026, 22, 151–157, doi:10.3762/bjoc.22.8

• with the steric effect of the tert-butyl group of the catalyst, is responsible for the high stereoselectivity of the reaction. Keywords: aromatic imine; asymmetric catalysis; Mannich reaction; noncovalent interactions; organocatalysis; Introduction The Mannich reaction, i.e., the addition of an

• malonate. It is known that N-atoms are the strongest XB acceptors in electroneutral compounds [26]. It has also been shown that imines protected with heteroarylsulfonyl groups provide higher enantioselectivity than those protected with the more commonly used phenylsulfonyl or tosyl groups in addition

Design and synthesis of an axially chiral platinum(II) complex and its CPL properties in PMMA matrix

• Daiki Tauchi,
• Sota Ogura,
• Misa Sakura,
• Kazunori Tsubaki and
• Masashi Hasegawa

Beilstein J. Org. Chem. 2026, 22, 143–150, doi:10.3762/bjoc.22.7

• %. Synthesis of S/R-3 Under an argon atmosphere. S-2 (197 mg, 0.389 mmol) in tetrahydrofuran (1.7 mL) was treated with a dropwise addition of 1 M TBAF solution (16.7 mL, 16.7mmol), and the resulting solution was stirred at room temperature for 2 hours. After the addition of water, the mixture was extracted

Symmetrical D–π–A–π–D indanone dyes: a new design for nonlinear optics and cyanide detection

• Ergin Keleş,
• Alberto Barsella,
• Nurgül Seferoğlu,
• Zeynel Seferoğlu and
• Burcu Aydıner

Beilstein J. Org. Chem. 2026, 22, 131–142, doi:10.3762/bjoc.22.6

• theory (DFT) methods. The dyes also exhibit chemosensor properties, showing selectivity for cyanide via a Michael addition mechanism that causes the disappearance of the ICT band, and a significant color change was observed in both organic and aqueous media. In addition, the interaction mechanism between

• ). The vinyl bridges were added to the design, which have the potential to open nucleophilic addition reactions (Michael type) due to their electron deficiencies, in addition to acting as π-bridges for the D–A conjugation. Furthermore, a symmetric design with increased π-conjugation was planned to shift

• under ambient light. In addition, interaction mechanisms of dyes with cyanide were studied using the 1H NMR titration method, and it was determined that they interacted through an addition mechanism. Photophysical properties and interaction mechanisms of the compounds were also supported through density

Highly electrophilic, gem- and spiro-activated trichloromethylnitrocyclopropanes: synthesis and structure

• Ilia A. Pilipenko,
• Mikhail V. Grigoriev,
• Olga Yu. Ozerova,
• Igor A. Litvinov,
• Darya V. Spiridonova,
• Aleksander V. Vasilyev and
• Sergey V. Makarenko

Beilstein J. Org. Chem. 2026, 22, 123–130, doi:10.3762/bjoc.22.5

• –C2H protons of the cyclopropane ring (3JH(1)H(2) = 5.7–7.5 Hz) indicate their transoid arrangement [38][39][45]. This makes it possible to assign 1SR,2RS configurations to the stereocenters. The proposed mechanism for this transformation is depicted in Scheme 6. Michael addition of the CH-acid anion I

Total synthesis of natural products based on hydrogenation of aromatic rings

• Haoxiang Wu and
• Xiangbing Qi

Beilstein J. Org. Chem. 2026, 22, 88–122, doi:10.3762/bjoc.22.4

• -art systems depend on expensive transition metals such as platinum, ruthenium, or palladium, inflating the cost of large-scale applications. In addition, precious-metal catalysts often display poor selectivity, while heteroatoms in heteroarenes – acting as Lewis bases – tend to coordinate to the metal

• systems. In addition, converting a planar sp2-hybridized-atoms-enriched framework into three-dimensional sp3-hybridized-atoms-enriched architectures inherently generates new stereocenters, making stereocontrol essential in asymmetric variants. As highlighted in the methods below, recent advances in

• of axially chiral cyclic compounds with high enantioselectivity could be synthesized. In addition, the authors also obtained central chiral cyclic compounds by asymmetric hydrogenation of phenanthrene with directing groups. In 2022 and 2024, Chirik and co-workers reported the use of molybdenum as a

Advances in Zr-mediated radical transformations and applications to total synthesis

• Hiroshige Ogawa and
• Hugh Nakamura

Beilstein J. Org. Chem. 2026, 22, 71–87, doi:10.3762/bjoc.22.3

• intramolecular addition to the olefin, affording the cyclized acetal product 4. The reaction proceeded efficiently across a range of substrates bearing various substituents at R¹–R⁴, delivering the desired cyclized products 4a–f in good yields. The proposed mechanism is illustrated in Scheme 1C. Initially

• transmetallation with a NiII complex generated by oxidative addition of the thioester to Ni0. Finally, reductive elimination from NiII furnishes the ketone. Given the strong Zr–S bond (BDE = 137 kcal/mol) [12], zirconocene is thought to play a key role in facilitating the oxidative addition of Ni0 to the thioester

• its subsequent radical addition to 2-methylene-1,3-dithiane (14) proceeded, affording radical intermediate 15. This radical intermediate rapidly underwent homodimerization to give vic-bis(dithiane) 16. The reaction could be applied to both tertiary and secondary alkyl halides, providing the

Reactivity umpolung of the cycloheptatriene core in hexa(methoxycarbonyl)cycloheptatriene

• Dmitry N. Platonov,
• Alexander Yu. Belyy,
• Rinat F. Salikov,
• Kirill S. Erokhin and
• Yury V. Tomilov

Beilstein J. Org. Chem. 2026, 22, 64–70, doi:10.3762/bjoc.22.2

• further transformation in the case of allylation. Reactions with diazonium salts mainly involve a vicinal addition of the reagent to the anion and subsequent 1,5-sigmatropic shift, 6π-electrocyclization, and azocyclopropane rearrangement into dihydroindazole derivatives. Analysis of the reaction

Synthesis and applications of alkenyl chlorides (vinyl chlorides): a review

• Daniel S. Müller

Beilstein J. Org. Chem. 2026, 22, 1–63, doi:10.3762/bjoc.22.1

• Vertex Pharmaceuticals describes the synthesis of alkenyl chloride 21 on a 360 and 580 mmol scale (Scheme 6A) [51]. The addition of a few drops of DMF was not commented. Surprisingly a significant decrease in yield was observed at the larger 580 mmol scale compared to the 360 mmol scale. Scott reported a

• is generated in situ and likely present only in trace amounts. All our attempts to accelerate the reaction through addition of various mono- and bidentate phosphorus ligands were unsuccessful. A similar trend was observed with NEt3, which afforded optimal yields at 20–30 mol % loading (not shown

• unable to efficiently separate 61 from side product 94, which was likely formed via addition of acetyl chloride to 61 followed by conversion of the ketone to the alkenyl chloride. Regarding the mechanism (Scheme 18B), acid-catalyzed enolization of the ketone is proposed (enol I), followed by acetylation