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

• tetrahedral value which results in a large ring strain of 25.5 kcal/mol, comparable to oxirane (27.3 kcal/mol) and much greater than tetrahydrofuran (5.6 kcal/mol) [4]. Moreover, the strained C–O–C bond angle effectively exposes the oxygen lone pairs, making oxetane a strong hydrogen-bond acceptor and Lewis

• base [5]. In fact, its hydrogen-bond-accepting ability is even stronger than that of the other 3-, 5- and 6-membered cyclic ethers, as well as the carbonyls of aldehydes, ketones, esters and carbonates [6][7][8]. The only better carbonyl-based hydrogen-bond acceptors are amides, carbamates and ureas [9

• (Figure 2) [10][11][12]. As for the analogy to carbonyls, oxetanes display comparable polarity, spatial arrangement of the oxygen lone pairs and hydrogen-bond-accepting ability. In addition, they possess one major advantage and that is greater metabolic stability: while carbonyl groups are susceptible to

Gold extraction at the molecular level using α- and β-cyclodextrins

• Susana Santos Braga

Beilstein J. Org. Chem. 2025, 21, 1116–1125, doi:10.3762/bjoc.21.89

• by hydrogen-bond interactions and oriented in alternating head-to-head and tail-to-tail modes comprising a continuous channel filled by an alternating [K(OH2)6]+ and [AuBr4]− polyionic chain (Figure 1). The authors further demonstrated that the process is selective for gold by determining, using ICP

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

• . Similarly, Rajendran and Rajan (2024) utilized catalytic DABCO to perform the esterification of cinnamamide 99, where DABCO acted as a hydrogen-bond acceptor for phenol (Scheme 43B) [82]. Yuan-Yong and co-workers (2022) reported a DABCO/Fe3O4-catalyzed N-methyl amidation of cinnamic acid 122 via cooperation

On the photoluminescence in triarylmethyl-centered mono-, di-, and multiradicals

• Daniel Straub,
• Markus Gross,
• Mona E. Arnold,
• Julia Zolg and
• Alexander J. C. Kuehne

Beilstein J. Org. Chem. 2025, 21, 964–998, doi:10.3762/bjoc.21.80

Silver(I) triflate-catalyzed post-Ugi synthesis of pyrazolodiazepines

• Muhammad Hasan,
• Anatoly A. Peshkov,
• Syed Anis Ali Shah,
• Andrey Belyaev,
• Chang-Keun Lim,
• Shunyi Wang and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2025, 21, 915–925, doi:10.3762/bjoc.21.74

• attention due to their modular hydrogen bond donor/acceptor profile that can be tuned by varying the nitrogen position and the degree of unsaturation as well as by fusion with other rings [3]. Benzodiazepines, which contain a seven-membered diazepine core fused to a benzene ring, are recognized as

Recent advances in controllable/divergent synthesis

• Jilei Cao,
• Leiyang Bai and
• Xuefeng Jiang

Beilstein J. Org. Chem. 2025, 21, 890–914, doi:10.3762/bjoc.21.73

• single-electron transfer with substrate 72 to form radical intermediate Int-70, completing the DPZ catalytic cycle. Intermediate Int-70 adds to substrate 73 to form radical intermediate Int-71, which further adds to hydrogen-bond-activated substrate 74 to form hydrogen-bonded complex Int-72. When Na3PO4

4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches

• Nguyen Tran Nguyen,
• Vo Viet Dai,
• Luc Van Meervelt,
• Do Thi Thao and
• Nguyen Minh Thong

Beilstein J. Org. Chem. 2025, 21, 817–829, doi:10.3762/bjoc.21.65

• a dihedral angle of 49.86(10) 86.22(11)° with the phenyl rings C6–C11 and C18–C23, respectively. The angle between both phenyl rings is 70.76(11)°. The stereochemistry around the double bond is Z, allowing an intramolecular N–H···O hydrogen bond between one of the carbonyl oxygen atoms and the amino

• enhance its interaction with iNOS via the optimization of the hydrogen bond with Cys200. These results highlight the potential of compound 5e as a lead compound for further development in targeting iNOS-related pathologies. Experimental results have confirmed that compound 5e is a promising candidate for

• ellipsoids at the 30% probability level. The intramolecular hydrogen bond is shown as red dashed line. The bioavailability radar of studied compounds 5a–e. The interactions of potential drugs 5a–c in the active site of enzyme iNOS. The interactions of potential drugs 5d and 5e and control drug (DEX) in the

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

• fluorophore derivatives bind the Pepper aptamer with affinities in the low nanomolar range [12]. Crystal structure analyses revealed that in the ligand binding pocket, a characteristic hydrogen bond is formed between the hydroxy group of the N-hydroxyethyl substituent of HBC and the N7 of G41 [12][13]. We

• -dimensional structure of the Pepper binding site with a bound HBC derivative (pdb code 7EOM). The hydrogen bond between N7 of guanine in position 41 (G41) and the hydroxy group of HBC is highlighted as gray dashed line [12]; d) concept for covalent attachment of HBC fluorophores to the N7 atom of G41 of the

Study of the interaction of 2H-furo[3,2-b]pyran-2-ones with nitrogen-containing nucleophiles

• Constantine V. Milyutin,
• Andrey N. Komogortsev and
• Boris V. Lichitsky

Beilstein J. Org. Chem. 2025, 21, 556–563, doi:10.3762/bjoc.21.44

• intramolecular hydrogen bond between the NH-unit and the carbonyl group. The presented results indicate that the reaction of the aliphatic amine doesn’t lead to recyclization of the studied heterocyclic system. Further, we hypothesized that synthesis of the enamine 4a can be realized in one-pot variant without

Unprecedented visible light-initiated topochemical [2 + 2] cycloaddition in a functionalized bimane dye

• Metodej Dvoracek,
• Brendan Twamley,
• Mathias O. Senge and
• Mikhail A. Filatov

Beilstein J. Org. Chem. 2025, 21, 500–509, doi:10.3762/bjoc.21.37

• bimanes studied: a) Cl2B (B), representing 90% of the disordered asymmetric unit, b) Me2B, not disordered with dotted line representing an intramolecular hydrogen bond, and c) Me4B showing the majority occupied (55%) N–N moiety. View of the molecular structure in the crystal of a) symmetry generated by

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

• obtained as a single stereoisomer and in quantitative yield after 80 h of irradiation. The role of 2.2 is to create a close-packed environment via hydrogen-bond interactions where the [2 + 2] photodimerization can occur stereoselectively. Next, the authors evaluated the possibility of using the template

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

• constriction (ground-state destabilization) are also possible [140][168][169][170]. The metals can sometimes participate in redox catalysis [171], and may be stabilized by the cage structure [160][172][173][174]. The organic part of the MOC has also been levied as a hydrogen-bond donor to activate an

• [329][330][331], superbases [332][333][334][335][336], or non-specific arrays of hydrogen-bond donors [337]/acceptors [338]. Advances in post-assembly modifications [339] have recently allowed stable organic cages featuring endohedral (internally directed) functionality [340][341], or metals [342][343

The effect of neighbouring group participation and possible long range remote group participation in O-glycosylation

• Rituparna Das and
• Balaram Mukhopadhyay

Beilstein J. Org. Chem. 2025, 21, 369–406, doi:10.3762/bjoc.21.27

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

• tropolone ring proton, which appears at 6.9 ppm. A characteristic specificity of the 1H NMR spectra of compounds 7 and 8 is the presence of signals of hydroxy group protons forming a strong hydrogen bond with the indoline nitrogen atom, which closes the six-membered chelate cycle. These signals are observed

• increase in the intramolecular hydrogen bond length NH···O of the (NH) isomers and a decrease in the magnitude of hydrogen bond N···HO of the (OH) forms (Figure 1). On the other hand, the position of the benzoannelated fragment does not significantly affect the structural and energetic parameters of the

• the previously obtained 2-(indolin-2-yl)-1,3-tropolone)). The angle between the planes C(2)C(3)C(6)C(7) and (3)C(4)C(5)C(6) is equal to 27.6° (34°). In compound 7b, as in 2-(indolin-2-yl)-1,3-tropolone, an intramolecular hydrogen bond N(1)–H(1)···O(2) was realized with parameters: distances N–H = 0.86

Streamlined modular synthesis of saframycin substructure via copper-catalyzed three-component assembly and gold-promoted 6-endo cyclization

• Asahi Kanno,
• Ryo Tanifuji,
• Satoshi Yoshida,
• Sota Sato,
• Saori Maki-Yonekura,
• Kiyofumi Takaba,
• Jungmin Kang,
• Kensuke Tono,
• Koji Yonekura and
• Hiroki Oguri

Beilstein J. Org. Chem. 2025, 21, 226–233, doi:10.3762/bjoc.21.14

• - and E- rings serve as hydrogen bond (HB) donors/acceptors to facilitate DNA alkylation at C21. UV–vis absorption (gray solid line), the emission spectrum (blue solid line), and the corresponding excitation spectrum (blue dashed line) of the imidate 18 in CHCl3 (c = 100 μM). aQuantum yield (Φfl

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

• was observed at an average wavelength of 384 nm for 5a–e, 439 nm for 6a–e and 430 nm for 7a–e (see Supporting Information File 1 for detailed information). In support of the proposed scaffold 7b, we were able to solve its crystal structure (Figure 3). An intermolecular bifurcated hydrogen bond network

Quantifying the ability of the CF₂H group as a hydrogen bond donor

• Matthew E. Paolella,
• Daniel S. Honeycutt,
• Bradley M. Lipka,
• Jacob M. Goldberg and
• Fang Wang

Beilstein J. Org. Chem. 2025, 21, 189–199, doi:10.3762/bjoc.21.11

• group can act as a hydrogen bond donor, serving as a potential surrogate for OH or SH groups but with a weaker hydrogen bond donation ability. Here, we describe a series of CF2H group-containing moieties that facilitate hydrogen bond interactions. We survey hydrogen bond donation ability using several

• established methods, including 1H NMR-based hydrogen bond acidity determination, UV–vis spectroscopy titration with Reichardt's dye, and 1H NMR titration using tri-n-butylphosphine oxide as a hydrogen bond acceptor. Our experiments reveal that the direct attachment of the CF2H group to cationic aromatic

• systems significantly enhances its hydrogen bond donation ability, a result consistent with theoretical calculations. We anticipate that this chemistry will be valuable for designing functional molecules for chemical biology and medicinal chemistry applications. Keywords: bioisostere; difluoromethyl

Hydrogen-bonded macrocycle-mediated dimerization for orthogonal supramolecular polymerization

• Wentao Yu,
• Zhiyao Yang,
• Chengkan Yu,
• Xiaowei Li and
• Lihua Yuan

Beilstein J. Org. Chem. 2025, 21, 179–188, doi:10.3762/bjoc.21.10

• and G1. The brown dotted lines show the hydrogen bond distance between H2 and the positively charged region of G1 (d[C–H···O] = 2.2–3.5 Å). The red dotted lines show the hydrogen bond distance between H2 and the proton of the phenyl group of G1 (d[C–H···O] = 2.7–2.9 Å). c) Dimeric structure showing

Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

• acids feature as the most prolific catalytic structure. The last part of the article discusses hydrogen-bond-donating catalysts and other catalyst motifs such as phase-transfer catalysts. Keywords: asymmetric organocatalysis; atropoisomers; atroposelective synthesis; axial chirality; stereogenic axis

• to NHC-catalyzed reactions. The major part is devoted to chiral Brønsted acid catalysis as it seems so far the most widely used activation principle for the generation of axially chiral compounds. Hydrogen-bond-donating catalysts and various other activation modes complete the discussion of recent

• and di-tert-butyl azodicarboxylate (Scheme 22) [45]. An added benefit to these products is that they possess an intramolecular hydrogen bond acting as a stabilizing factor and products 68 were prepared in good to very good yields and excellent enantiomeric purities. Based on the authors’ design

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

• nitrogen atom which is prone to interacting with hydrogen-bond donors or Brønsted acids decreasing the LUMO energy of the diene. This review article aims to give an overview of the non-covalent organocatalyzed cyclization reactions involving α,β-unsaturated imines. Although most of the cyclization

• covered in this review are hydrogen-bond donors such as thioureas and squaramides, Brønsted bases such as tertiary amines, and Brønsted acids such as chiral phosphoric acids. As depicted in Figure 4, a bifunctional squaramide is able to activate both an α,β-unsaturated imine through hydrogen bonding with

• reviews [17][18]. Review Hydrogen bond donors: bifunctional thioureas and squaramides The use of bifunctional catalysts is commonplace in organocatalyzed transformations [19][20][21][22][23]. These catalysts are able to activate an electrophile and a nucleophile simultaneously and in IEDADA reactions they

Synthesis of extended fluorinated tripeptides based on the tetrahydropyridazine scaffold

• Thierry Milcent,
• Pascal Retailleau,
• Benoit Crousse and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2024, 20, 3174–3181, doi:10.3762/bjoc.20.262

• groups (CF3 or CF2H) in organic molecules can modulate their physicochemical (pKa, lipophilicity), structural (additional hydrophobic and hydrogen-bond interactions), and biological properties (metabolic stability, membrane permeability) [14][15]. Alongside the very well-known CF3 group, the CF2H group

• has become an essential structural motif in medicinal chemistry due to its hydrogen-bond donor capacity, its lipophilic character, and as a bioisostere for alcohol, thiol, or amine groups [16][17][18][19]. Thus, the contribution of fluorinated compounds to pharmaceuticals has been crucial for more

• configuration of compounds 7e and 7e’ and consequently of tripeptides 8e and 8e’ (see Supporting Information File 1). Next, some preliminary conformational studies were performed. Firstly, the X-ray crystallographic analysis of compound 8f did not show any hydrogen-bond pattern and the global structure of the

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• oxazepane scaffold 11 (Scheme 11). Replacing the nitrogen in the bioactive lactam 11 (γ-secretase inhibitor in AD therapy) with an oxygen should reduce the hydrogen bond donating (HBD) ability of the compounds. The method employs readily available starting materials, resulting in the desired compounds in a

• single step. The oxazepine scaffold can be easily accessed using the Ugi four-component reaction. By modifying this scaffold, the researchers aimed to reduce the hydrogen-bond donating properties. The Passerini reaction, employing bifunctional salicylaldehydes and isocyanides successfully yielded

• of the nitrogen in lactams 11 with an oxygen in 12 to influence hydrogen-bond donating properties and synthesis of the benzodioxepinone derivatives via Passerini reaction. MCR 3 + 2 reaction to develop spirooxindole, spiroacenaphthylene, and bisbenzo[b]pyran compounds. Synthesis of ML192 analogs

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

• that function as hydrogen-bond donors and acceptors. Additionally, the nitrogen atoms in the pyrrole units of the porphyrin structure can also act as Lewis bases, capable of donating electron pairs. These properties enable tetrapyrrolic macrocycles to act as effective binding sites or catalytically

• addition of furan-based silyloxydiene synthons to a variety of achiral aldehydes using four different calix[4]pyrrole macrocycles (3, 4, 11, and 12) as organocatalysts (Figure 3) [38]. These calixpyrrole macrocycles acted as hydrogen-bond donors, activating substrate aldehydes through hydrogen-bonding

• concluded that both the presence of hydrogen-bond donor moieties (pyrrolic –NH groups) and a basic β-substituent are necessary to make the compound catalytically active. Further, authors have performed 1H NMR binding and kinetic studies and suggested that the reaction mechanism involves a simultaneous

Enantioselective regiospecific addition of propargyltrichlorosilane to aldehydes catalyzed by biisoquinoline N,N’-dioxide

• Noble Brako,
• Sreerag Moorkkannur Narayanan,
• Amber Burns,
• Layla Auter,
• Valentino Cesiliano,
• Rajeev Prabhakar and
• Norito Takenaka

Beilstein J. Org. Chem. 2024, 20, 3069–3076, doi:10.3762/bjoc.20.255

• (Figure 1a). This suggests that the isomerization is not energetically feasible on its own. However, in the presence of N,N-diisopropylethylamine this process can occur readily. In the reactant (Rprop in Figure 1b), the nitrogen atom of N,N-diisopropylethylamine forms a hydrogen bond with the H1 proton of

Structure and thermal stability of phosphorus-iodonium ylids

• Andrew Greener,
• Stephen P. Argent,
• Coby J. Clarke and
• Miriam L. O’Duill

Beilstein J. Org. Chem. 2024, 20, 2931–2939, doi:10.3762/bjoc.20.245

• Information File 1, Figure S6), the Kamlet–Taft hydrogen bond acceptor ability (β) (Supporting Information File 1, Figure S7) [37], the pKa of the conjugate acid HX (Figure S8), or the anion’s position (axial vs equatorial). The main stabilising factor we identified was the torsion angle φ between the