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

Recent advances and future challenges in the bottom-up synthesis of azulene-embedded nanographenes

• Bartłomiej Pigulski

Beilstein J. Org. Chem. 2025, 21, 1272–1305, doi:10.3762/bjoc.21.99

• and co-workers demonstrated that also BN heterocycles can be obtained using similar types of precursors (Scheme 23) [107]. Compound 179 was reacted with PhBCl2 to yield BN heterocycle 180 in 78% yield. Compound 180 exhibits high sensitivity for the visual detection of fluoride ions and undergoes an

Recent advances in oxidative radical difunctionalization of N-arylacrylamides enabled by carbon radical reagents

• Jiangfei Chen,
• Yi-Lin Qu,
• Ming Yuan,
• Xiang-Mei Wu,
• Heng-Pei Jiang,
• Ying Fu and
• Shengrong Guo

Beilstein J. Org. Chem. 2025, 21, 1207–1271, doi:10.3762/bjoc.21.98

• difunctionalization of N-arylacrylamides has emerged as a powerful strategy for the construction of diverse nitrogen-containing heterocycles, particularly oxindoles and related scaffolds. This review provides a comprehensive summary of recent advances in oxidative radical difunctionalization of N-arylacrylamides with

Salen–scandium(III) complex-catalyzed asymmetric (3 + 2) annulation of aziridines and aldehydes

• Linqiang Wang and
• Jiaxi Xu

Beilstein J. Org. Chem. 2025, 21, 1087–1094, doi:10.3762/bjoc.21.86

• -containing five-membered saturated heterocycles. They are not only useful building blocks for the synthesis of biologically active compounds [1], for example, side-chain precursor of paclitaxel [2], but also widely exist in some pharmaceuticals [3][4], such as antibacterial agents of Gram-positive organisms

Synthesis of pyrrolo[3,2-d]pyrimidine-2,4(3H)-diones by domino C–N coupling/hydroamination reactions

• Ruben Manuel Figueira de Abreu,
• Robin Tiedemann,
• Peter Ehlers and
• Peter Langer

Beilstein J. Org. Chem. 2025, 21, 1010–1017, doi:10.3762/bjoc.21.82

• . Keywords: alkynes; catalysis; cyclizations; domino reactions; heterocycles; Introduction Pyrimidines and purines are one of the most important heterocyclic compounds with prevalent biological functions. Both are found in nucleosides and their corresponding polymeric DNA and RNA, and hence are vital for

Recent total synthesis of natural products leveraging a strategy of enamide cyclization

• Chun-Yu Mi,
• Jia-Yuan Zhai and
• Xiao-Ming Zhang

Beilstein J. Org. Chem. 2025, 21, 999–1009, doi:10.3762/bjoc.21.81

• cyclization modes that provide entries to various N-heterocycles, some of which serve as key structural motifs in natural alkaloids. This review highlights recent advancements in enamide-based cyclization reactions, including enamide–alkyne cycloisomerization, [3 + 2] annulation, and polycyclization, with a

• principles, tandem reactions or annulations can be designed to efficiently access N-heterocycles. As the enamides are also easily accessible via condensations, applications of these nitrogen-containing building blocks in the synthesis of N-heterocycles are synthetically straightforward. When applied properly

• . Cyclization/isomerization – collective total synthesis of fawcettimine-type alkaloids The bicyclic decahydroquinoline enamide motif can serve as a versatile precursor to access different types of tricyclic N-heterocycles. As demonstrated in the above work from She’s group, the aza-Prins cyclization renders

Study of tribenzo[b,d,f]azepine as donor in D–A photocatalysts

• Katy Medrano-Uribe,
• Jorge Humbrías-Martín and
• Luca Dell’Amico

Beilstein J. Org. Chem. 2025, 21, 935–944, doi:10.3762/bjoc.21.76

• behavior is supported by the DFT studies, which suggested a better spatial separation between the HOMO and LUMO. As expected, the HOMO–LUMO energy gap followed a trend that is dependent on the electron-donating capacity of the nitrogen heterocycles and amine present in compounds 5e (2.9 eV), 5d (3.5 eV

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

• isocyanides, followed by a silver(I) triflate-catalyzed intramolecular heteroannulation of the resulting pyrazole-tethered propargylamides occurring in a 7-endo-dig fashion. The approach is scalable and tolerates a diverse range of substitution patterns. Keywords: heterocycles; post-MCR transformations

• ; pyrazolodiazepines; silver catalysis; Ugi reaction; Introduction Synthetic chemists are continuously involved in the development of methodologies for accessing new heterocyclic scaffolds that resemble naturally occurring products and biologically active molecules [1][2]. Nitrogen heterocycles draw particular

• synthetic methods to access diazepines fused with other nitrogen-containing heterocycles towards their broader exploration in high-throughput screening for identifying new drug candidates. Traditional synthetic methods for producing medium-ring nitrogen-containing heterocycles often involve complex

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

• , Vietnam Academy of Science and Technology (VAST), Hanoi 10072, Vietnam 10.3762/bjoc.21.65 Abstract Pyrrolidine-2,3-diones are important intermediates in the synthesis of numerous nitrogen-containing heterocycles which possess a broad spectrum of biological and pharmacological activities. In this article

Synthesis and photoinduced switching properties of C₇-heteroatom containing push–pull norbornadiene derivatives

• Daniel Krappmann and
• Andreas Hirsch

Beilstein J. Org. Chem. 2025, 21, 807–816, doi:10.3762/bjoc.21.64

• catalytic back-conversion studies. Keywords: heterocycles; molecular solar thermal systems; norbornadiene; photochemistry; quadricyclane; Introduction In recent decades, the demand for renewable energy has increased tremendously [1]. A promising alternative to fossil fuels is the utilization of so-called

Regioselective formal hydrocyanation of allenes: synthesis of β,γ-unsaturated nitriles with α-all-carbon quaternary centers

• Seeun Lim,
• Teresa Kim and
• Yunmi Lee

Beilstein J. Org. Chem. 2025, 21, 800–806, doi:10.3762/bjoc.21.63

• are important intermediates in organic syntheses because of the versatility of the cyano group, which can be readily transformed into a wide range of functional groups, including amides, carboxylic acids, amines, aldehydes, ketones, and N-heterocycles [6][7][8]. However, the synthesis of all-carbon

New advances in asymmetric organocatalysis II

• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 766–769, doi:10.3762/bjoc.21.60

• organocatalytic cycloaddition reactions of unsaturated imines. A broad variety of activation modes, as well as catalyst structures, was covered and found to be useful in affording a diverse array of chiral N-heterocycles [27]. In my group, we recently became interested in atroposelective catalytic syntheses

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

• amine (e.g., a fluorinated analogue of the antidepressant drug, citalopram 93 [160]). We now turn our attention to cyclic amines. Fluorine has been shown to be capable of modifing the conformations of a variety of N-heterocycles, ranging in size from four- to eight-membered rings [48][161][162][163]. In

Entry to 2-aminoprolines via electrochemical decarboxylative amidation of N‑acetylamino malonic acid monoesters

• Olesja Koleda,
• Janis Sadauskis,
• Darja Antonenko,
• Edvards Janis Treijs,
• Raivis Davis Steberis and
• Edgars Suna

Beilstein J. Org. Chem. 2025, 21, 630–638, doi:10.3762/bjoc.21.50

• facilitated the cyclization, and the 6-membered heterocycles 6h,i could be obtained in 27% and 18% yield, respectively. In addition to sulfonamides, carbamates such as N-Boc and benzamide are also suitable as nucleophiles for the anodic decarboxylation/cyclization reaction. However, the corresponding 2

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

• concerns and improved reaction control can be addressed, paving the way for more efficient and sustainable synthetic methodologies. Keywords: cascade reactions; formaldehyde surrogates; green chemistry; heterocycles; multicomponent reactions; Introduction Organic chemistry is a mature discipline that has

• 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

• 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

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

• ][9]. Wherein, the wide variety of easily available starting butenolides and amines allows one to create a huge array of practically useful products. At the same time, the application of hydrazine derivatives expands the range of formed heterocycles. So, along with the aforementioned N-substituted