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

Computational design for enantioselective CO₂ capture: asymmetric frustrated Lewis pairs in epoxide transformations

• Maxime Ferrer,
• Iñigo Iribarren,
• Tim Renningholtz,
• Ibon Alkorta and
• Cristina Trujillo

Beilstein J. Org. Chem. 2024, 20, 2668–2681, doi:10.3762/bjoc.20.224

• an in silico approach to design asymmetric frustrated Lewis pairs (FLPs) aimed at controlling reaction stereochemistry. Four FLP scaffolds, incorporating diverse Lewis acids (LA), Lewis bases (LB), and substituents, were assessed via volcano plot analysis to identify the most promising catalysts. By

• significantly and seeks to explore new possibilities in this area. Herein, the present study focusses on the asymmetric insertion of CO2 into PO using asymmetric FLPs as catalysts. Initially, five FLP scaffolds with different substituents, LA and LB, were tested, resulting in a total of 53 potential catalysts

• (Scheme 1). The most promising catalyst scaffolds for the reaction under study were identified by volcano plot analysis [26][27]. Inspired by the asymmetric oxazoline synthesised by Gao et al. [28], and guided by the volcano plot results, modifications to these FLP scaffolds facilitated the development of

Synthesis and cytotoxicity studies of novel N-arylbenzo[h]quinazolin-2-amines

• Battini Veeraiah,
• Kishore Ramineni,
• Dabbugoddu Brahmaiah,
• Nangunoori Sampath Kumar,
• Hélène Solhi,
• Rémy Le Guevel,
• Chada Raji Reddy,
• Frédéric Justaud and
• René Grée

Beilstein J. Org. Chem. 2024, 20, 2592–2598, doi:10.3762/bjoc.20.218

• scaffolds for bioactive molecules. Thus, it appeared interesting to explore novel molecules with extended aromatic units around this basic quinazoline core and our first choice was N-arylbenzo[h]quinazoline-2-amines with the general structure C as indicated in Figure 1. Very limited studies have been

Anion-dependent ion-pairing assemblies of triazatriangulenium cation that interferes with stacking structures

• Yohei Haketa,
• Takuma Matsuda and
• Hiromitsu Maeda

Beilstein J. Org. Chem. 2024, 20, 2567–2576, doi:10.3762/bjoc.20.215

• . Moreover, the N-aryl-substituted TATA+ cations have been used as the building units of porous organic polymers for capturing CO2 [27]. Cations with characteristic electron-deficient planar triangular geometries were used as scaffolds for various supramolecular cage structures [28][29]. Although

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

• representative examples to illustrate the potential of electrochemistry or photoelectrochemistry for the LSF of valuable molecular scaffolds. Keywords: electrochemistry; late-stage functionalization; paired electrolysis; pharmaceutical drugs; photoelectrochemistry; Introduction Organic electrochemistry is

• achieved compared to many classical methods. In light of the general trend towards more chemoselective protocols with broader functional group compatibility, there has been a growing interest in exploring the potential of electrosynthesis for the late-stage functionalization of complex scaffolds

• carbocation intermediate, which rearomatizes through proton loss. Concurrently, the cathodic reduction of the generated protons produces H2. In addition to (hetero)aromatic groups, alkene scaffolds also underwent this reaction (Scheme 3). In the same year, the Lei group [10] extended the electrochemical C(sp2

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

• a result, developing an alternative strategy would be an attractive solution to address the limitations described above. Flow chemistry was chosen as the most attractive alternative for the photo-induced (visible light) Achmatowicz rearrangement to convert furfuryl alcohol scaffolds into

HFIP as a versatile solvent in resorcin[n]arene synthesis

• Hormoz Khosravi,
• Valeria Stevens and
• Raúl Hernández Sánchez

Beilstein J. Org. Chem. 2024, 20, 2469–2475, doi:10.3762/bjoc.20.211

• described herein exemplifies that even when protocols are well-established, a simple, yet critical modification may improve access to known species in shorter reaction times, and most importantly unveil new scaffolds that were previously inaccessible. We encourage scientists starting their careers in this

Photoredox-catalyzed intramolecular nucleophilic amidation of alkenes with β-lactams

• Valentina Giraldi,
• Giandomenico Magagnano,
• Daria Giacomini,
• Pier Giorgio Cozzi and
• Andrea Gualandi

Beilstein J. Org. Chem. 2024, 20, 2461–2468, doi:10.3762/bjoc.20.210

• literature, oxacepham scaffolds, the 6-membered fused bicyclic analog of clavams, were prepared from appropriately substituted unfused precursors by intramolecular C-radical addition to alkene functionalities [44]. The utilization of radical conditions has prevented the effective nucleophilic opening of the

Synthesis, electrochemical properties, and antioxidant activity of sterically hindered catechols with 1,3,4-oxadiazole, 1,2,4-triazole, thiazole or pyridine fragments

• Daria A. Burmistrova,
• Andrey Galustyan,
• Nadezhda P. Pomortseva,
• Kristina D. Pashaeva,
• Maxim V. Arsenyev,
• Oleg P. Demidov,
• Mikhail A. Kiskin,
• Andrey I. Poddel’sky,
• Nadezhda T. Berberova and
• Ivan V. Smolyaninov

Beilstein J. Org. Chem. 2024, 20, 2378–2391, doi:10.3762/bjoc.20.202

• heterocycles are classified as privileged medicinal scaffolds being components of many drugs [13][14]. Thiazole derivatives and their reduced forms exhibit antitumor (thiazofurin, ixabepilone), antibacterial (cefotaxime, ceftaroline, cefiderocol), antifungal (isavuconazole, fosravuconazole), antiviral