Thiazolidinones: novel insights from microwave synthesis, computational studies, and potentially bioactive hybrids

• Luan A. Martinho,
• Victor H. J. G. Praciano,
• Guilherme D. R. Matos,
• Claudia C. Gatto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2025, 21, 2618–2636, doi:10.3762/bjoc.21.203

• (intramolecular charge transfer) process. Keywords: fluorescence; hybridization; imidazo[1,2-a]pyridines; Knoevenagel reaction; thiazolidinone; Introduction Heterocycles are compounds of significant interest to organic chemists as drug candidates due to their already widespread presence in many commercially

• scaffolds for several synthetic or natural compounds [5]. Five-membered heterocycles include the thiazolidinone nucleus, characterized by two heteroatoms and a carbonyl group on the fourth carbon, as seen in compounds like rhodanine and thiazolidine-2,4-dione derivatives (Figure 1). These privileged

Visible-light-driven NHC and organophotoredox dual catalysis for the synthesis of carbonyl compounds

• Vasudevan Dhayalan

Beilstein J. Org. Chem. 2025, 21, 2584–2603, doi:10.3762/bjoc.21.200

• Studer et al., which belongs to the class of aryl and heteroaryl electrophilic substitutions and is a highly versatile synthetic transformation in traditional organic chemistry. A highly regioselective dual catalytic approach for the novel acylation of electron-rich benzo-fused arenes or heterocycles 15

Pentacyclic aromatic heterocycles from Pd-catalyzed annulation of 1,5-diaryl-1,2,3-triazoles

• Kaylen D. Lathrum,
• Emily M. Hanneken,
• Katelyn R. Grzelak and
• James T. Fletcher

Beilstein J. Org. Chem. 2025, 21, 2524–2534, doi:10.3762/bjoc.21.194

• Kaylen D. Lathrum Emily M. Hanneken Katelyn R. Grzelak James T. Fletcher Department of Chemistry and Biochemistry, Creighton University, 2500 California Avenue, Omaha, NE 68178, USA 10.3762/bjoc.21.194 Abstract A series of pentacyclic aromatic heterocycles representing functionalized

• observed for these annulated molecules, while their analogous non-annulated control compounds were not bioactive. Keywords: annulation; arenes; antimicrobials; fused-ring systems; UV–vis spectroscopy; Introduction Polycyclic aromatic heterocycles are a diverse class of small molecules with utility in a

• , there remains a wide range of chemical space representing these heterocycles that has not yet been explored. Hence, there is an ongoing interest in identifying synthetic strategies to access unreported ring structures and in characterizing the resulting physical and biological properties of such

Palladium-catalyzed regioselective C1-selective nitration of carbazoles

• Vikash Kumar,
• Jyothis Dharaniyedath,
• Aiswarya T P,
• Sk Ariyan,
• Chitrothu Venkatesh and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2025, 21, 2479–2488, doi:10.3762/bjoc.21.190

• developed a regioselective protocol for the direct C1–H nitration of carbazoles, an important class of heterocycles with wide-ranging applications in materials science and natural products chemistry. The transformation proceeds using commercially available Pd2(dba)3 as the catalyst and silver nitrate as the

Ex-situ generation of gaseous nitriles in two-chamber glassware for facile haloacetimidate synthesis

• Nikolai B. Akselvoll,
• Jonas T. Larsen and
• Christian M. Pedersen

Beilstein J. Org. Chem. 2025, 21, 2465–2469, doi:10.3762/bjoc.21.188

• of various trifluoromethyl-containing aza-heterocycles, such as pyridines [2], pyridinones and pyrimidinones [3], tetrazoles [4], tetrazapentalenes [5] and uracil [6]. In addition, it has also been used for the synthesis of fluoro-substituted ketones [7] and substituted trifluoroacetamides via the

• sufficient to be used in a subsequent reaction, hence demonstrating the advantage of using a two-chamber system compared to a one-pot setup, where excess reagents would be present in the crude. As mentioned in the introduction, trifluoroacetonitrile is often used to synthesize a variety of heterocycles via

Transformation of the cyclohexane ring to the cyclopentane fragment of biologically active compounds

• Natalya Akhmetdinova,
• Ilgiz Biktagirov and
• Liliya Kh. Faizullina

Beilstein J. Org. Chem. 2025, 21, 2416–2446, doi:10.3762/bjoc.21.185

• % yield. Jin et al. [85] reported an efficient photoinduced carboborative ring contraction of monounsaturated six-membered carbo- and heterocycles, allowing the regio- and stereoselective synthesis of functionalized cyclopentanes at gram scales. This method leads to the formation of compounds with

Recent advances in Norrish–Yang cyclization and dicarbonyl photoredox reactions for natural product synthesis

• Peng-Xi Luo,
• Jin-Xuan Yang,
• Shao-Min Fu and
• Bo Liu

Beilstein J. Org. Chem. 2025, 21, 2315–2333, doi:10.3762/bjoc.21.177

• congested structures in complex bicyclic systems. 2 Alkaloids 2.1 Lycoplatyrine A In 2020, Sarpong's group disclosed their progress toward a robust and broadly applicable strategy for the C–H functionalization of piperidines and related saturated N-heterocycles. This approach involves lactamization via

• ring, constructing 86 – setting the stage for the group’s key reaction, in which α-hydroxy-β-lactams (e.g., 87) serve as surrogates for α-metalated N-heterocycles in Pd-catalyzed coupling with aryl halides. Both enantiomers of 87 (only one shown in Scheme 10) participated in a Pd-catalyzed

• epimers. This strategy merges photochemical selectivity with cross-coupling efficiency, avoiding reactive metal incompatibility and enabling precise stereocontrol for chiral nitrogen heterocycles. 3 Antibiotics 3.1 Synthetic study toward γ-rubromycin Since 2017, Suzuki's group has developed a

Pathway economy in cyclization of 1,n-enynes

• Hezhen Han,
• Wenjie Mao,
• Bin Lin,
• Maosheng Cheng,
• Lu Yang and
• Yongxiang Liu

Beilstein J. Org. Chem. 2025, 21, 2260–2282, doi:10.3762/bjoc.21.173

• radical initiated intramolecular cascade cyclization of 1,n-enynes to provide structurally diverse heterocycles (Scheme 4) [11]. Solvent selection dictated divergent reaction pathways under I2/TBHP oxidation. When an acetonitrile/water mixed solvent was used, iodine radical addition to the alkyne

• 2021, the Shibata group reported a gold-catalyzed ring isomerization strategy to synthesize medium-sized nitrogen heterocycles (Scheme 12) [19]. The seven-membered dibenzo[b,d]azepine and eight-membered dibenzo[b,d]azocine frameworks were successfully obtained through the modulation of alkyne terminal

• polycyclic aromatic heterocycles (Scheme 15) [23]. Catalysts bearing the strong σ-donating IPr ligand exhibited a marked preference for the 5-exo-dig cyclization pathway, affording five-membered ring product 70 (Scheme 15, path a). When a bulky Me4XPhos ligand was employed, the reaction favored 6-endo-dig

Thiadiazino-indole, thiadiazino-carbazole and benzothiadiazino-carbazole dioxides: synthesis, physicochemical and early ADME characterization of representatives of new tri-, tetra- and pentacyclic ring systems and their intermediates

• Gyöngyvér Pusztai,
• László Poszávácz,
• Anna Vincze,
• András Marton,
• Ahmed Qasim Abdulhussein,
• Judit Halász,
• András Dancsó,
• Gyula Simig,
• György Tibor Balogh and
• Balázs Volk

Beilstein J. Org. Chem. 2025, 21, 2220–2233, doi:10.3762/bjoc.21.169

• metabolic stability of the most promising derivatives was also determined using human liver microsomes. Keywords: early ADME characterization; Fischer indole cyclization; heterocycles; indoles; lead-likeness; new ring systems; physicochemical characterization; Introduction Considering the published

Synthesis of triazolo- and tetrazolo-fused 1,4-benzodiazepines via one-pot Ugi–azide and Cu-free click reactions

• Xiaoming Ma,
• Zijie Gao,
• Jiawei Niu,
• Wentao Shao,
• Shenghu Yan,
• Sai Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2025, 21, 2202–2210, doi:10.3762/bjoc.21.167

• of compounds 6a (red) and 8a (blue). Ugi–azide reaction for the synthesis of 1,5-DS-T-containing heterocycles. Proposed Ugi–azide-initiated synthesis of polyheterocyclic scaffolds 7 and 8. 4-CR vs stepwise Ugi–azide reactions for the synthesis of 7a. Synthesis of benzodiazepines 7a–k. Reaction

Electrochemical cyclization of alkynes to construct five-membered nitrogen-heterocyclic rings

• Lifen Peng,
• Ting Wang,
• Zhiwen Yuan,
• Bin Li,
• Zilong Tang,
• Xirong Liu,
• Hui Li,
• Guofang Jiang,
• Chunling Zeng,
• Henry N. C. Wong and
• Xiao-Shui Peng

Beilstein J. Org. Chem. 2025, 21, 2173–2201, doi:10.3762/bjoc.21.166

• synthesis of cyclic compounds have emerged. The electrochemical functionalization of alkynes was highlighted by Ahmed in 2019 [109], Zhang described radical annulation of 1,n-enynes under photo/electrochemical reaction conditions in 2023 [110], the electrochemical formation of heterocycles was summarized by

• Sindhu in 2022 [98] and sustainable syntheses of heterocycles from alkyne annulations through C–H activations were reported by Ackermann in 2024 [111]. Although few examples about the electrochemical formation of five-membered rings from alkynes were included in the above reviews [106][111], a systemic

Multicomponent reactions IV

• Thomas J. J. Müller and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2025, 21, 2082–2084, doi:10.3762/bjoc.21.163

• focused Reviews on heterocycles, reactivity patterns, and the role of MCRs as enabling tools at the interface with biosciences underscore the timeliness and enduring elegance of this powerful and concise concept in molecular synthesis. As the guest editors of this thematic issue, we would like to thank

Discovery of cytotoxic indolo[1,2-c]quinazoline derivatives through scaffold-based design

• Daniil V. Khabarov,
• Valeria A. Litvinova,
• Lyubov G. Dezhenkova,
• Dmitry N. Kaluzhny,
• Alexander S. Tikhomirov and
• Andrey E. Shchekotikhin

Beilstein J. Org. Chem. 2025, 21, 2062–2071, doi:10.3762/bjoc.21.161

• heterocyclic scaffolds are widely used in the treatment of various diseases, making them a common focus of research [1]. A substantial part of these compounds incorporate five- or six-membered nitrogen heterocycles. The indole and quinazoline cores represent two pharmacologically significant heterocyclic

• diverse therapeutic areas, including oncology (gefitinib, erlotinib), antiviral therapy (delavirdine, umifenovirum), CNS disorders (sertindole), and other directions (tadalafil) [4][5]. The annelation of quinazoline with nitrogen-containing heterocycles at the N(3)–C(4) bond represents a strategically

Switchable pathways of multicomponent heterocyclizations of 5-amino-1,2,4-triazoles with salicylaldehydes and pyruvic acid

• Yana I. Sakhno,
• Oleksander V. Buravov,
• Kostyantyn Yu. Yurkov,
• Anastasia Yu. Andryushchenko,
• Svitlana V. Shishkina and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2025, 21, 2030–2035, doi:10.3762/bjoc.21.158

• devoted to the study of the reactions of aminoazoles, pyruvic acid and its derivatives with salicylaldehydes and it was found that depending on the conditions (reaction time, temperature, and method of process activation, in particular ultrasound and microwave irradiation), different types of heterocycles

• case of aldehyde 2b, the MCR always led to the formation of a mixture of products 5d and 6d. Attempts to synthesize 5d and 6d as individual compounds under various conditions were unsuccessful. In addition, it was found that compounds 5 can be converted into oxygen-bridged heterocycles 4 after 1 hour

• control of the reaction, while oxygen-bridged heterocycles 4 are formed under thermodynamic control. The purity and structure of compounds 4 and 5 were established by elemental analysis, mass spectrometry, 1H and 13C NMR spectroscopy, and X-ray diffraction study (Figure 1). For example, the 1H NMR spectra

Aryl iodane-induced cascade arylation–1,2-silyl shift–heterocyclization of propargylsilanes under copper catalysis

• Rasma Kroņkalne,
• Rūdolfs Beļaunieks,
• Armands Sebris,
• Anatoly Mishnev and
• Māris Turks

Beilstein J. Org. Chem. 2025, 21, 1984–1994, doi:10.3762/bjoc.21.154

• stabilized allyl cation intermediates that undergo regioselective trapping by internal O- and N-nucleophiles furnishing functionalized heterocycles. This method provides access to tetrahydrofuran or pyrrolidine frameworks, each bearing a trifunctionalized (E)-configured vinyl side chain. The use of a shorter

• containing N-heterocycles, such as pyridine and pyrazole, provided the non-arylated tetrahydrofuran 12 as the main reaction product (Scheme 3), which is likely formed via the protodecupration pathway. However, to our delight the thiophenyl group was successfully added to the propargylsilane with 34% yield by

• -product. In the absence of a base, the protodecupration pathway is predominant, affording non-arylated heterocycles 12–14 instead. When considering shorter carbon chain-containing acylamides 16a–c as starting materials, we expected a similar cyclization pattern, involving imidate formation [10]. Instead

Stereoselective electrochemical intramolecular imino-pinacol reaction: a straightforward entry to enantiopure piperazines

• Margherita Gazzotti,
• Fabrizio Medici,
• Valerio Chiroli,
• Laura Raimondi,
• Sergio Rossi and
• Maurizio Benaglia

Beilstein J. Org. Chem. 2025, 21, 1897–1908, doi:10.3762/bjoc.21.147

• , and a ceramic diaphragm [44]. This method was found to be effective for synthesizing trans-2,3-diarylpiperazines through the intramolecular reductive coupling of 1,2-diimines and seven- and eight-membered heterocycles which were obtained in moderate to good yields via the cyclization of 1,3- and 1,4

Photoswitches beyond azobenzene: a beginner’s guide

• Michela Marcon,
• Christoph Haag and
• Burkhard König

Beilstein J. Org. Chem. 2025, 21, 1808–1853, doi:10.3762/bjoc.21.143

• Azoheteroarenes are azoswitches of which at least one aromatic ring is a heteroarene (Figure 3). The variety of heterocycles and substitution patterns that can be used gives rise to a considerable number of variants covering all the UV and visible spectrum and with thermal Z-isomer lifetimes that span from

• photophysical properties of this photoswitch class. The vast possibility of combinations and the straightforward syntheses make these compounds extremely attractive, however, somewhat difficult to strictly categorise: among the azoheteroarenes we find mainly nitrogen-based heterocycles such as pyrazole, pyrrole

• , pyridine, and indole, alongside with less common oxygen and sulphur-based heterocycles such as thiophene, thiazole, oxazole. At the end of the section, we will also briefly discuss heteroarylimines which, although not being azo-switches, resemble the geometry of azo-compounds and possess similar

Fe-catalyzed efficient synthesis of 2,4- and 4-substituted quinolines via C(sp²)–C(sp²) bond scission of styrenes

• Prafull A. Jagtap,
• Manish M. Petkar,
• Vaishnavi R. Sawant and
• Bhalchandra M. Bhanage

Beilstein J. Org. Chem. 2025, 21, 1799–1807, doi:10.3762/bjoc.21.142

• features of this protocol include the use of O2 as an ideal, green oxidant, operational simplicity and scalability, high atom- and step-economy, and cost-effectiveness, collectively enabling the single-step synthesis of two medicinally relevant N-heterocycles in excellent combined yields. Keywords: C–C

• strategies have been explored in recent decades for the synthesis of structurally diverse quinolines. Among them, transition-metal-catalyzed multicomponent reactions (MCRs) have emerged as particularly effective for constructing complex quinoline-based heterocycles [26][27][28]. Catalytic pathways such as

• styrene, leading to the in situ generation of two valuable intermediates that act as dual synthons for the synthesis of 2,4- and 4-substituted quinolines. As part of our ongoing efforts to develop innovative C–C and C–H activation strategies for constructing nitrogen-containing heterocycles [55][56], we

[3 + 2] Cycloaddition of thioformylium methylide with various arylidene-azolones in the synthesis of 7-thia-3-azaspiro[4.4]nonan-4-ones

• Daniil I. Rudik,
• Irina V. Tiushina,
• Anatoly I. Sokolov,
• Alexander Yu. Smirnov,
• Alexander R. Romanenko,
• Alexander A. Korlyukov,
• Andrey A. Mikhaylov and
• Mikhail S. Baranov

Beilstein J. Org. Chem. 2025, 21, 1791–1798, doi:10.3762/bjoc.21.141

• fluoride, is used for the synthesis of spirocyclic derivatives from arylidene-azolones. Four types of the corresponding heterocycles have been studied. A series of 7-thia-3-azaspiro[4.4]nonan-4-ones was obtained with yields varying from 17 to 99%. The stereochemical study revealed selective formation of

• single either cis or trans stereoisomers, dependent on the heterocycle core used. Keywords: arylidene-azolones; cycloaddition; nitrogen heterocycles; sulfur heterocycles; thioformylium methylide; Introduction Spirocyclic derivatives of heterocycles occupy an important place in modern organic and

• bioorganic chemistry [1]. Such substances are actively investigated in drug design, since their rigid 3D structure allows them to bind more selectively and effectively to biological targets in comparison to classical planar heterocycles [1][2][3][4][5]. Spirocyclic derivatives containing at least one five

Transition-state aromaticity and its relationship with reactivity in pericyclic reactions

• Israel Fernández

Beilstein J. Org. Chem. 2025, 21, 1613–1626, doi:10.3762/bjoc.21.125

• used transformation in synthesis, typically leading to five-membered heterocycles [86][87]. Although introduced by Huisgen in 1960 [88][89][90], this process has experienced a new renaissance in the last decades due to its countless applications in different fields, and particularly in bioorthogonal

• chemistry [91][92][93]. Among the number of dipolarophiles compatible with this [3 + 2]-cycloaddition, phosphaalkynes [94][95][96] and arsaalkynes [97] have been recently used because they allow easy access to novel heterocycles. For instance, when using organic azides as dipoles, the transformation leads

3-Aryl-2H-azirines as annulation reagents in the Ni(II)-catalyzed synthesis of 1H-benzo[4,5]thieno[3,2-b]pyrroles

• Julia I. Pavlenko,
• Pavel A. Sakharov,
• Anastasiya V. Agafonova,
• Derenik A. Isadzhanyan,
• Alexander F. Khlebnikov and
• Mikhail S. Novikov

Beilstein J. Org. Chem. 2025, 21, 1595–1602, doi:10.3762/bjoc.21.123

• reaction, in which 2H-azirines act as the annulation reagent. Keywords: annulation; azirines; benzothiophenes; indoles; nickel catalysis; Introduction 2H-Azirines represent a valuable class of nitrogen heterocycles that are widely used as versatile building blocks in organic synthesis. In particular, the

• -containing compounds [1][2][3]. Such reactions can be initiated by electrophilic, nucleophilic or radical reagents, photoirradiation or proceed under acid-, metal-, or photocatalytic conditions. This strategy of azirine ring expansion is applicable to the synthesis of a variety of 4‒9-membered N-heterocycles

• , differing in the nature and number of heteroatoms and their mutual arrangement. These also include ortho-fused heterocycles, which are obtained from functionalized cyclic systems and azirines as annulation reagents. Significant progress has been achieved in the synthesis of pyrrolo-fused systems by the

Ambident reactivity of enolizable 5-mercapto-1H-tetrazoles in trapping reactions with in situ-generated thiocarbonyl S-methanides derived from sterically crowded cycloaliphatic thioketones

• Grzegorz Mlostoń,
• Małgorzata Celeda,
• Marcin Palusiak,
• Heinz Heimgartner,
• Marta Denel-Bobrowska and
• Agnieszka B. Olejniczak

Beilstein J. Org. Chem. 2025, 21, 1508–1519, doi:10.3762/bjoc.21.113

• ]. Thiocarbonyl S-methanides (thiocarbonyl ylides) 1, which were first reported in the 1980s by R. Huisgen and co-workers contributed to a substantial extension of mechanistic interpretations of cycloaddition reactions and to rapid development of methods applied not only for the synthesis of sulfur heterocycles

• five-membered heterocycles via [3 + 2]-cycloaddition reactions. Depending on the type of the dipolarophile used in these reactions, the target heterocycles may contain only one sulfur atom (cycloadditions with C=C or C≡C dipolarophiles) or more heteroatoms (cycloadditions with C=S, C=O, C=N, N=N, S=O

• , respectively [2][6]. On the other hand, enolizable imidazole-2-thiones and pyrimidine-2-thione were reported to react with 1a and 1b yielding S,S-dithioacetals as exclusive trapping/insertion products [12] (Scheme 1). Notably, enolizable nitrogen heterocycles such as imidazole and pyrazole, or bicyclic

High-pressure activation for the solvent- and catalyst-free syntheses of heterocycles, pharmaceuticals and esters

• Kelsey Plasse,
• Valerie Wright,
• Guoshu Xie,
• R. Bernadett Vlocskó,
• Alexander Lazarev and
• Béla Török

Beilstein J. Org. Chem. 2025, 21, 1374–1387, doi:10.3762/bjoc.21.102

• hydrostatic pressure (HHP) was found to be an efficient activation method in several catalyst- and solvent-free reactions and has found application for the syntheses of heterocycles and the preparation of active pharmaceutical ingredients (APIs) via acylation and acid- and solvent-free esterification. The

• of important heterocycles, the synthesis of well-known APIs, such as acetaminophen and acetylsalicylic acid, a variety of esterification reactions and the successful scale up (up to 100 g scale) of the Paal–Knorr reaction. The use of HHP appears to provide several advantages, for example, resulting

• . Water is used as a pressure transmitting medium that has relatively low compressibility, readily available, and non-toxic. Results and Discussion HHP-assisted synthesis of 1,3-dihydrobenzimidazoles Heterocycles are extremely versatile compounds and are used as building blocks for fine chemicals and

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

• stable isosteric replacements for gem-dimethyl and carbonyl groups. This work reviews possible synthetic strategies towards these strained heterocycles, covering both de novo constructions of the 4-membered ring as well as derivatisations of oxetane building blocks, then reactivity of oxetanes in terms

• –2021, Kuduk and co-workers published three different tandem, one-pot methodologies towards complex polycyclic heterocycles [100][101][102]. All of them are two-step reactions consisting of an intermolecular coupling followed by an intramolecular, base-induced oxetane opening (Scheme 48). The first one

• reaction is assumed to proceed via an initial SN1 substitution of the tertiary alcohol followed by intramolecular opening of the oxetane ring. The authors further demonstrated the wide scope of this methodology by preparing spirocyclic and fused bicyclic dioxanes as well as sulphur-containing heterocycles

Recent advances in amidyl radical-mediated photocatalytic direct intermolecular hydrogen atom transfer

• Hao-Sen Wang,
• Lin Li,
• Xin Chen,
• Jian-Li Wu,
• Kai Sun,
• Xiao-Lan Chen,
• Ling-Bo Qu and
• Bing Yu

Beilstein J. Org. Chem. 2025, 21, 1306–1323, doi:10.3762/bjoc.21.100

• require electrophilic heterocycles. These limitations hinder the broader application of such systems. Alexanian’s group modified amidyl radical precursors by incorporating halogen atoms, transforming them into bifunctional reagents. The HAT component of amidyl radical precursors was facilitated by amidyl