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

• hydrogen bonding with Cys200. These results underscore the potential of 4-(1-methylamino)ethylidenepyrrolidine-2,3-diones, especially compound 5e, as promising scaffolds for the development of anti-inflammatory agents targeting iNOS-related pathologies. Keywords: anti-inflammatory pyrrolidine-2,3-dione

• -disubstituted pyrrolidine-2,3-diones as scaffolds for the development of anti-inflammatory agents targeting iNOS-related pathologies. Results and Discussion Synthesis of 4-(1-methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones 5a–e The reaction between 4-acetyl-3-hydroxy-1,5-disubstituted-3

Copper-catalyzed domino cyclization of anilines and cyclobutanone oxime: a scalable and versatile route to spirotetrahydroquinoline derivatives

• Qingqing Jiang,
• Xinyi Lei,
• Pan Gao and
• Yu Yuan

Beilstein J. Org. Chem. 2025, 21, 749–754, doi:10.3762/bjoc.21.58

• report the copper-catalyzed synthesis of tetrahydroquinoline derivatives via a domino reaction of aniline with cyclobutanone oxime. This method demonstrates a selective approach for generating bioactive tetrahydroquinoline scaffolds, which have broad applications in pharmaceutical chemistry. The reaction

• stereocontrol (Scheme 1b) [24]. In 2023, Zeng et al. reported the first example of a chromium-catalyzed spirocyclization between anilines and cyclobutanones, providing direct access to medicinally relevant cyclobutane-annulated and structurally constrained spirotetrahydroquinoline (STHQ) scaffolds [25]. Given

• -catalyzed method for the synthesis of spirotetrahydroquinoline (STHQ) derivatives via the reaction of anilines with cyclobutanone oxime. This protocol offers a straightforward approach to constructing structurally diverse STHQ scaffolds under mild conditions, with broad substrate scope and high functional

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

• scaffolds – alkanes – then we will progress to ethers, alcohols, sugars, amines (and their derivatives), carbonyl compounds, peptides, and finally sulfur-containing compounds. By arranging the material in this way, we hope that newcomers to the field might be able to readily envisage ways to apply these

• concepts to their own scaffolds of interest. Review 1 Alkanes The simplest organic scaffolds are the alkanes. In such molecules, C–C bond rotations often have low energy barriers, and they often deliver conformers that are similar in energy, and this means that many alkanes have considerable conformational

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

• the MCR product is possible thus increasing the versatility of these reactions in terms of structural diversity and molecular complexity. In this context, a wide variety of heterocycles and macrocycles as important biological scaffolds have been synthesized [6]. One of the most important components

• . Synthesis of heteroaromatic systems One of the most powerful applications of MCRs is the synthesis of heterocyclic compounds and several reports in recent years showed the advantages of using this tool as a synthetic strategy to generate complex molecular scaffolds with medicinal relevance [25][26][27]. In

• the cyclization process producing various highly diverse nitrogen-containing heterocycles, which are valuable scaffolds in medicinal chemistry [46]. Synthesis of non-aromatic heterocycles As stated above, DMSO can also hydrolytically decompose to formaldehyde. There are many examples of reactions in

Asymmetric synthesis of β-amino cyanoesters with contiguous tetrasubstituted carbon centers by halogen-bonding catalysis with chiral halonium salt

• Yasushi Yoshida,
• Maho Aono,
• Takashi Mino and
• Masami Sakamoto

Beilstein J. Org. Chem. 2025, 21, 547–555, doi:10.3762/bjoc.21.43

• , Chiba 263-8522, Japan 10.3762/bjoc.21.43 Abstract β-Amino cyanoesters are important scaffolds because they can be transformed into useful chiral amines, amino acids, and amino alcohols. Halogen bonding, which can be formed between halogen atoms and electron-rich chemical species, is attractive because

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

• tetracyclic steroid scaffolds such as 17β-estradiol [18], where the diazocine core mimics the framework of the bioactive compound (Figure 1a). The other option is to attach the diazocine photoswitch as a substituent (appendix) to the biologically active molecule (Figure 1b) [6][10][19][20][21]. The art of

• switching properties even in an aqueous environment and are therefore promising switches in photopharmacological applications. a) Structural similarity of N-acetyl diazocine 1 with known 17βHSD3-inhibitor tetrahydrodibenzazocine (THB) [17] and parent diazocine with steroid scaffolds [18]. b) Parent

New tandem Ugi/intramolecular Diels–Alder reaction based on vinylfuran and 1,3-butadienylfuran derivatives

• Yuriy I. Horak,
• Roman Z. Lytvyn,
• Andrii R. Vakhula,
• Yuriy V. Homza,
• Nazariy T. Pokhodylo and
• Mykola D. Obushak

Beilstein J. Org. Chem. 2025, 21, 444–450, doi:10.3762/bjoc.21.31

• environmentally friendly synthetic strategies, especially one-pot multicomponent and tandem reactions, are key to modern organic and medicinal chemistry [1][2][3][4][5][6][7] and have proven to be successful in generating diverse heterocyclic scaffolds, as highlighted in a recent book [8]. Multicomponent

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

• ]. Chemists thus turned toward scaffolds that were easier to access [36][111]. Self-assembled containers, capsules, nanoreactors In the 1990s, Rebek popularized “softball”/”tennis ball” reactors [112][113][114]. These “capsules” [115][116][117] are two or more molecules that self-assemble via hydrogen bonds

• formation possible in metal–ligand bonding provides chemists with a shortcut to access 3D scaffolds. When well-designed linkers and metals are combined, discrete cages emerge as the thermodynamic product (Figure 5A) [22][142][143][144]. Typically, rigid linkers are required to enforce geometry, although a

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

• prepared scaffolds are valuable additions to the class of pyrazolo-1,2-benzothiazine antibiotics with selective antistaphylococcal activity. Keywords: acetamides; antibiotics; antimicrobial; benzothiazines; Staphylococcus aureus; Introduction The global crisis of antibiotic resistance has been

• resistance [2]. Innovative scaffolds for novel antibiotic drug candidates are required to create new methods for safe and effective treatments. Chemically designed drug leads can complement naturally found antibiotics and may engage multiple modes of action and might have a longer lifetime before resistance

• evolves [3]. Complex chemical scaffolds with more than one protein-engaging functionality in a single molecule are advantageous for selectivity. This concept of synergistic compounds and complex chemical interactions helps to boost biological activity and prolongs the emergence of resistance in pathogens

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

• or side reactivity in a scope of around 50 examples with yields ranging from 27 to 97 % compared to the use of blue-light (Scheme 3a) [20]. In this way, T. Rovis et al. have exploited their photocatalytic system on the functionalization of drug-like scaffolds with moderate to good yields (Scheme 3b

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

• of lower oxidation state aromatic rings at the A- and E-rings of saframycins. Rational and systematic modification of both ends of the THIQ scaffolds would facilitate the development of reversible covalent DNA binders with tailored sequence preferences. Biosynthetically, the pentacyclic core scaffold

• reliance on the biomimetic PS reactions, we sought to develop a de novo synthetic process that is independent of the substituents on the aromatic rings at both ends (Scheme 1c). To achieve more rapid synthesis and flexible structural diversification of the alkaloidal scaffolds, we conceived a streamlined

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

• specific MCR-based scaffolds as precursors and employing the abundant and inexpensive formamide as a C1 feedstock under neat conditions, we were able to efficiently access substituted thieno-, quinolino- and indolopyrimidones without the need of column chromatography. Further, a single-crystal X-ray

• ]. In addition, carbonyldiimidazole-based heteroannulations via MCRs have been reported, giving access to drug like scaffolds [21][22][23][24]. However, their employment in C1 chemistry should and could be advanced. Herein, we point out formamide as an alternative relevant building block for C1

• chemistry by using specific, suitably functionalized MCR scaffolds. This positions formamides as versatile, synthetic hubs towards privileged scaffolds and high-end chemicals. Over the years, the reactivity of formamide has been widely explored in heterocyclic chemistry, but it has only recently started to

Dioxazolones as electrophilic amide sources in copper-catalyzed and -mediated transformations

• Seungmin Lee,
• Minsuk Kim,
• Hyewon Han and
• Jongwoo Son

Beilstein J. Org. Chem. 2025, 21, 200–216, doi:10.3762/bjoc.21.12

• , dioxazolones containing free -OH groups exhibited excellent functional group tolerance, leading to the formation of primary amides 28g and 28h. Moreover, biologically relevant scaffolds on dioxazolones were successfully transformed in this transformation (28i–k). As illustrated in Figure 9, a catalytic cycle

• late-stage functionalizations of complex scaffolds such as peptides, drug molecules, and natural products containing unprotected free OH and NH groups are anticipated. Proposed reaction pathway for the copper-catalyzed synthesis of δ-lactams from dioxazolones. Proposed reaction mechanism for the copper

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

• % CuCl2 catalyst was required, and anodic oxidation was employed instead of stoichiometric chemical oxidants. This cascade strategy is compatible with various substituted N-arylenamines 57 that bear electron-withdrawing and electron-donating groups, facilitating the production of quinoxaline scaffolds 59

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

• kinetic resolution through a Pictet–Spengler reaction, enabled the preparation of axially chiral 8-aryltetrahydroisoquinolines 108 starting from aminobiaryl scaffolds 107 and paraformaldehyde (Scheme 34) [59]. For most substrates, excellent enantioselectivities and moderate to excellent yields were

• of the naphthol's OH group and indole's NH group, presumably through hydrogen bonding with organocatalyst C27. The organocatalytic atroposelective preparation of promising EBINOL scaffolds 167 and 169 was done by Wang et al. with the help of the SPINOL-derived organocatalysts C40, C41, and C42

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

• substituted β-nitrostyrenes. This one-pot procedure allows the quick isolation of substituted β-nitrostyrene scaffolds with 62–83% yield under mild conditions, without the need for special precautions, inert atmosphere, and time-consuming purification techniques. Keywords: 2C-X; CuCl2; NaBH4; β-nitrostyrene

• aluminum hydride, sodium borohydride is a non-pyrophoric and easy-to-handle reducing agent. Since the first attempts in 1967, NaBH4 has been employed to reduce β-nitrostyrene scaffolds to the corresponding nitroalkanes [19][20][21]. Several catalysts have been combined with NaBH4 to facilitate full

• -nitrostyrene (4a), precursor of most of the hallucinogenic 2C-X family (Table 1). This method was also tested on other types of scaffolds to investigate its potential general applications and effects on other substituents. As sodium borohydride per se does not reduce ester nor nitro functionalities [15][16][17

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

• functionalization (LSF) of peptide scaffolds. α,β-Unsaturated amino acids like dehydroalanine (Dha) derivatives have emerged as particularly useful structures, as the electron-deficient olefin moiety can engage in late-stage functionalization reactions, like a Giese-type reaction. Cheap and widely available

• ]. Amid the growing popularity of biomolecular drug candidates, the late-stage modification of peptide scaffolds has gained significant importance [28]. A particularly interesting class of amino acids for late-stage diversification consists of dehydroamino acids (Dha). Dha derivatives have shown

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

• imines; asymmetric organocatalysis; cyclization; N-heterocycles; inverse electron demand aza-Diels–Alder reaction; Introduction Nitrogen-containing heterocycles are abundant scaffolds present in natural products, biologically active compounds, pharmaceuticals, synthetic agrochemicals, and functional

• activation providing stereoselective syntheses to access chiral N-heterocyclic scaffolds. While those strategies involving hydrogen-bond donors such as bifunctional thioureas and squaramides or chiral Brønsted acids such as chiral phosphoric acids are more established, reports involving cinchona-derived

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

• synthesizing diverse scaffolds [6]. Furthermore, the Ugi reaction exhibits versatility in forming both fused and unfused heterocyclic compounds, involving 4-, 5-, 6-, and 7-membered rings [17]. This capability is exploited by various approaches, including the Ugi–Deprotection–Cyclization strategy (UDC) and

• AChE, while pyrazole scaffolds possess the ability to reduce the tau and β-amyloid dual aggregation. Benzofuran-pyrazole aldehydes were employed in the Ugi azide reaction to give the desired hybrids. From the screened compounds, 2a, 2b, 2c, 2d, 2e, and 2f demonstrated notable efficacy in regulating the

• agents for central nervous system pathologies. This combination not only enhances the pace of discovery but also broadens the scope of potential treatments, underscoring the significant impact of MCRs in medicinal chemistry. Classical MCRs. Different scaffolds that can be formed with the Ugi adduct. Most

Hypervalent iodine-mediated intramolecular alkene halocyclisation

• Charu Bansal,
• Oliver Ruggles,
• Albert C. Rowett and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 3113–3133, doi:10.3762/bjoc.20.258

• ; heterocycles; hypervalent iodine; oxidation; Introduction Halogenated carbocyclic and heterocyclic compounds are present in many active pharmaceutical ingredients [1][2]. The intramolecular halocyclisation of alkenes mediated by HVI(III) reagents allow access to a range of halogenated cyclic scaffolds in a

• cost effective and selective, one-pot transformation. Pharmaceutical uses for bio-active cyclic molecules accessible by I(III) reagents are plentiful; anticancer drugs can be formed from the basis of pyrrolo[2,3-b]indoles 1 [3][4], 2-oxazolines 2 [5][6], dihydrofuran 3 [7][8], and spirocyclic scaffolds

• heterocycles. Example bioactive compounds containing cyclic scaffolds potentially accessible by HVI chemistry. A general mechanism for HVI-mediated endo- or exo-halocyclisation. Metal-free synthesis of β-fluorinated piperidines 6. Ts = tosyl. Intramolecular aminofluorination of unactivated alkenes with a

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

• Metal-free tetrapyrrolic macrocycles as supramolecular organocatalysts Supramolecular organocatalysis has recently attracted emerging attention as a green alternative to metal-based catalysis [24][25][26]. Organocatalysis using macrocyclic scaffolds such as crown ethers, cyclodextrins, cucurbiturils

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

• Ritu Mamgain,
• Kokila Sakthivel and
• Fateh V. Singh

Beilstein J. Org. Chem. 2024, 20, 2891–2920, doi:10.3762/bjoc.20.243

• heteroaromatic compounds serve as crucial scaffolds in pharmaceuticals. Therefore, the synthesis of N-substituted heteroaromatic derivatives under mild and environmentally friendly conditions is highly valued. The use of electrophilic diaryliodonium salts for nitrogen arylation has been investigated. Working on

• approach providing regioselective access to N2-arylated products along with high yields. The synthetic route could also be applied for the synthesis of N2-arylbenzotriazoles which are promising scaffolds for pharmaceuticals. Subsequently, the impact of the aryl group present in the diaryl iodonium salts on

Synthesis of pyrrole-fused dibenzoxazepine/dibenzothiazepine/triazolobenzodiazepine derivatives via isocyanide-based multicomponent reactions

• Marzieh Norouzi,
• Mohammad Taghi Nazeri,
• Ahmad Shaabani and
• Behrouz Notash

Beilstein J. Org. Chem. 2024, 20, 2870–2882, doi:10.3762/bjoc.20.241

• , and triazolobenzodiazepine under solvent- and catalyst-free conditions. Purposefully, this approach produced various bioactive scaffolds using environmentally friendly, mild, and simple conditions. Due to their bioactive moieties, these compounds with exclusive fluorescence properties may attract

• isocyanides, gem-diactivated olefins, and cyclic imines (dibenzoxazepines, dibenzothiazepine, and triazolobenzodiazepine) under catalyst- and solvent-free conditions. Furthermore, the other advantages of this reaction include the manufacturing premium pharmaceutical scaffolds, a wide range of substrates

Copper-catalyzed yne-allylic substitutions: concept and recent developments

• Shuang Yang and
• Xinqiang Fang

Beilstein J. Org. Chem. 2024, 20, 2739–2775, doi:10.3762/bjoc.20.232

• sequence, [4 + 1] and [3 + 2] annulations involving yne-allylic substitutions have been released. These studies have shown the huge potential of this protocol in affording diversified molecular scaffolds, and more studies will be expected to demonstrate the value of this reaction. Copper-catalyzed allylic

Synthesis of spiroindolenines through a one-pot multistep process mediated by visible light

• Francesco Gambuti,
• Jacopo Pizzorno,
• Chiara Lambruschini,
• Renata Riva and
• Lisa Moni

Beilstein J. Org. Chem. 2024, 20, 2722–2731, doi:10.3762/bjoc.20.230

• Francesco Gambuti Jacopo Pizzorno Chiara Lambruschini Renata Riva Lisa Moni Department of Chemistry and Industrial Chemistry, University of Genoa, Via Dodecaneso 31, 1646 Genova, Italy 10.3762/bjoc.20.230 Abstract Spiro-heterocyclic indolenines are privileged scaffolds widely present in numerous

• : isocyanide; multicomponent reactions; one-pot reaction; oxidation; spiroindolenine; Ugi reaction; visible light; Introduction Diversity-oriented synthesis (DOS) is a successful approach to biologically active scaffolds directed to create an enormous exploratory space in pharmaceutical hit discovery [1][2