Synthesis of sterically shielded piperidine nitroxides via acid-catalyzed heterocyclization of β-aminoketone derivatives with ketones

• Mark M. Gulman,
• Yurii I. Glazachev and
• Sergey A. Dobrynin

Beilstein J. Org. Chem. 2026, 22, 948–954, doi:10.3762/bjoc.22.74

• ], followed by oxidation in the tungstate/hydrogen peroxide system [29]. It should be noted that no case of heterocyclization has ever been described where the resulting piperidine cycle contained three substituents at the 2- and 6-positions of the heterocycle. Subsequent treatment of these nitrones with

• -tetrapropyl-substituted piperidine nitroxides, and sterically shielded nitroxides with functional groups in the side chain of the heterocycle. Results and Discussion Aminodioxolanes 4a,b were obtained from enones 1a,b via a modified literature sequence [30] involving phthalimide Michael addition, dioxolane

• signals of the dioxolane moiety protons, confirming complete deprotection. The signal intensities for the methylene protons at the 3- and 5-positions of the heterocycle were remarkably diminished due to H/D exchange under the acidic conditions employed for sample preparation. All EPR spectra were

Palladium-catalyzed benzocyclization reactions of quinoline-2-carboxamides via sequential C–H/N–H functionalization

• Shoichi Sugita,
• Kentaro Okano and
• Atsunori Mori

Beilstein J. Org. Chem. 2026, 22, 905–914, doi:10.3762/bjoc.22.71

• corresponding heterocycle-fused compounds. The high chemoselectivity of the 1,2-dihaloarene functional groups is confirmed in this reaction, thus enabling divergent synthesis of various multifused heterocyclic systems. Keywords: C–H activation; chemodivergent synthesis; C–N coupling; fused-ring system

• ; sequential reaction; Introduction Cyclic structures comprising nitrogen-containing multifused rings are extremely important because such heterocycle-fused cyclic structures [1][2] are found in various advanced materials [3][4] and biologically essential molecules [5][6][7]. Quinoline is a particularly

• preparation of annulation precursors through o-brominated aniline derivatives [36][37][38][39][40][41]. Furthermore, the reported methodologies for synthesizing N-heterocycle-fused lactams are characterized by either low efficiency or protracted processes [42][43]. On the other hand, benzocyclization

Synthesis and structural elucidation of a novel bis-spirooxindole from isatin and ethylenediamine

• Irene Moreno-Gutiérrez,
• Josefa L. López-Martínez,
• Sonia Berenguel-Gómez,
• Irene Torres-García,
• Duane Choquesillo-Lazarte,
• Manuel Muñoz-Dorado,
• Miriam Álvarez-Corral and
• Ignacio Rodríguez-García

Beilstein J. Org. Chem. 2026, 22, 813–820, doi:10.3762/bjoc.22.63

• conditions. Keywords: ethylenediamine; isatin; spirooxindole; Introduction Isatin (1) is a highly versatile platform for heterocycle construction, particularly through skeletal editing, ring expansion, and related transformations that enable rapid access to complex molecular architectures [1]. In parallel

Synthesis of heterocycles based on azomethine ylides from α-amino acids (or amines) and carbonyl compounds

• Ekaterina V. Berezhnaya,
• Alexander I. Ponyaev,
• Vitali M. Boitsov and
• Alexander V. Stepakov

Beilstein J. Org. Chem. 2026, 22, 705–741, doi:10.3762/bjoc.22.55

• with a dipolarophile, such as an alkene or alkyne, to form a five-membered heterocycle in one step. Currently, this type of reaction allows for the efficient preparation of bi- and polycyclic fused or spiro-linked structures with multiple chiral centers and high regio- and stereocontrol [1][2][3][4

• of a five-membered N,O-bidentate metalated azomethine. At the same time, a suitable coordinating nitrogen-containing heterocycle, such as a 2-pyridyl group, can also provide sufficient activation via the formation of an N,N-bidentate metalated azomethine, which facilitates asymmetric cycloaddition

Synthesis and stereochemical analysis of dynamic planar chiral oxa[7]orthocyclophene

• Yukiho Hashimoto,
• Yuuya Kawasaki,
• Kazunobu Igawa and
• Katsuhiko Tomooka

Beilstein J. Org. Chem. 2026, 22, 436–442, doi:10.3762/bjoc.22.30

• successfully transformed into central chirality by epoxidation without loss of enantiomeric purity. Keywords: dynamic chirality; medium-sized heterocycle; orthocyclophene; planar chirality; stereochemical analysis; Introduction In the course of our study on planar chiral medium-sized cyclic molecules [1][2

Cone p-aminocalix[4]arenes enriched with ‘clickable’ alkyne or azide functionalities

• Ilia Korniltsev,
• Vasily Bazhenov,
• Alexander Gorbunov,
• Dmitry Cheshkov,
• Stanislav Bezzubov,
• Vladimir Kovalev and
• Ivan Vatsouro

Beilstein J. Org. Chem. 2026, 22, 399–415, doi:10.3762/bjoc.22.28

• -pentylated tetratosylureacalix[4]arene 52 [51] were acquired and analyzed. In terms of time-averaged molecular symmetry, tetraureacalix[4]arenes of three types were prepared in this work: Cs-symmetric calixarene 49 with one triazole heterocycle at the narrow rim, C2v-symmetric calixarenes 48 and 51 with

Design, synthesis and biological evaluation of 2,5-diaryloxazolo[4,5-d]pyrimidin-7-ylamines as selective cytotoxic agents against HeLa cells

• Maryna V. Kachaeva,
• Agnieszka B. Olejniczak,
• Marta Denel-Bobrowska,
• Victor V. Zhirnov,
• Yevheniia S. Velihina,
• Stepan G. Pilyo and
• Volodymyr S. Brovarets

Beilstein J. Org. Chem. 2026, 22, 390–398, doi:10.3762/bjoc.22.27

• pairs) can increase water solubility and facilitate salt formation. Introducing amino groups into heterocycles can have a significant impact on the anticancer activity of a compound [4][5]. Many studies have investigated the anticancer potential of heterocycle derivatives containing cytisine, glucamine

• K562 and EC109 cells (IC50 > 12 mM). In A549 and HepG2 cells, cytisine exhibited activity, with IC50 values of 4.40 ± 1.70 mM and 5.92 ± 2.77 mM, respectively [6]. Heterocycle hybrids with sugar moieties have shown selective cytotoxicity against liver cancer (HepG2 – IC50 values of 1.32–9.43 µM) and

Spirobarbiturates with a pyrrolizidine moiety: synthesis, structure and biological evaluation

• Arthur A. Puzyrkov,
• Andrew S. Drachuk,
• Ekaterina A. Popova,
• Alexander V. Stepakov and
• Vitali M. Boitsov

Beilstein J. Org. Chem. 2026, 22, 274–288, doi:10.3762/bjoc.22.20

• barbiturates [25]. Other methods include the DBU-mediated stereospecific cyclopropanation of barbiturate-based olefins with benzyl chlorides, developed by Chang’s group for the synthesis of spirobarbiturate-cyclopropanes [26]. Another interesting structural fragment is the pyrrolizidine heterocycle, which is a

Base-promoted deacylation of 2-acetyl-2,5-dihydrothiophenes and their oxygen-mediated hydroxylation

• Vladimir G. Ilkin,
• Margarita Likhacheva,
• Igor V. Trushkov,
• Tetyana V. Beryozkina,
• Vera S. Berseneva,
• Vladimir T. Abaev,
• Wim Dehaen and
• Vasiliy A. Bakulev

Beilstein J. Org. Chem. 2026, 22, 192–204, doi:10.3762/bjoc.22.13

• oxidative functionalization that does not disrupt the heterocycle or oxidize sulfur has not been previously reported. Dihydrothiophenes exhibit a broad spectrum of biological activity [47][48][49]. In this regard, the development of new routes for their modifications with the use of inexpensive and easily

Total synthesis of natural products based on hydrogenation of aromatic rings

• Haoxiang Wu and
• Xiangbing Qi

Beilstein J. Org. Chem. 2026, 22, 88–122, doi:10.3762/bjoc.22.4

• by substrate class (monocyclic vs fused; heterocycle vs carbocycle), all catalytic systems must still address the fundamental selectivity challenges inherent to arene reduction – chemo-, regio-, and stereoselectivity. Chemoselectivity becomes particularly demanding when reducible groups such as

• heterocycles exhibit strong Lewis basicity, potentially complexing and deactivating catalysts. Consequently, the catalytic hydrogenation of six-membered aromatic heterocycles such as pyridine often requires the introduction of substituents or activation of the aromatic heterocycle to facilitate hydrogenation

• heterocycle part: Quinoline, one of the most accessible heteroaromatic feedstocks from natural and commercial sources, has long attracted interest in both synthetic and medicinal chemistry. A central challenge, however, is the selective catalytic hydrogenation of quinolines to the synthetically valuable

Synthesis and applications of alkenyl chlorides (vinyl chlorides): a review

• Daniel S. Müller

Beilstein J. Org. Chem. 2026, 22, 1–63, doi:10.3762/bjoc.22.1

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

• compounds. The utility of click chemistry [11][12] for achieving chemoselective conjugation in a diversity of chemical environments has established the 1,2,3-triazole ring as a ubiquitous heterocycle in many research areas such as therapeutics [13][14][15][16], chemosensors [17][18][19], bioconjugation [20

• isoquinoline subunits. Heterocycle subunit identity and triazole C/N connectivity influenced the annulation reaction efficiency. Aromatic π-system expansion resulting from annulation was characterized by NMR, absorption and emission spectroscopy. Five benzotriazolophenanthroline regioisomers sharing structural

• reactivity of this family of pentacyclic aromatic heterocycles towards N-benzylation and the antimicrobial properties of such resulting quaternary ammonium compounds are ongoing. Examples of polycyclic aromatic heterocycle structures: phenanthridine (left), 1,5-naphthyridine (center), and 1,9-phenanthroline

Isoorotamide-based peptide nucleic acid nucleobases with extended linkers aimed at distal base recognition of adenosine in double helical RNA

• Grant D. Walby,
• Brandon R. Tessier,
• Tristan L. Mabee,
• Jennah M. Hoke,
• Hallie M. Bleam,
• Angelina Giglio-Tos,
• Emily E. Harding,
• Vladislavs Baskevics,
• Martins Katkevics,
• Eriks Rozners and
• James A. MacKay

Beilstein J. Org. Chem. 2025, 21, 2513–2523, doi:10.3762/bjoc.21.193

• , heterocycle of Db2 is rotated, placing its polar face towards solute and non-polar methyl group towards RNA. This results in the whole Db2 base being tilted, which breaks the intended stabilizing H-bond between the Db2 linker and the adjacent M. Db3 resulted in the best interaction in silico despite the low

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

• electrochemical [4 + 1] annulation of alkynoate with arylbenzimidazole [108], and the electrochemical ortho-annulation of 2-alkynylbenzenesulfonamide gave the corresponding five-membered heterocycle [106]. In recent years, a few reviews about the electrochemical cyclization of alkynes and electrochemical

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

• a strong emphasis on heterocycle synthesis. Beyond traditional condensation-based approaches, mechanistically innovative crossovers – linking metal catalysis with radical chemistry and, more recently, with photo(redox) catalysis – are opening entirely new avenues for MCR development. Finally, seven

α-Ketoglutaric acid in Ugi reactions and Ugi/aza-Wittig tandem reactions

• Vladyslav O. Honcharov,
• Yana I. Sakhno,
• Olena H. Shvets,
• Vyacheslav E. Saraev,
• Svitlana V. Shishkina,
• Tetyana V. Shcherbakova and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2025, 21, 2021–2029, doi:10.3762/bjoc.21.157

• ], antibacterial [8][14][15], and anticancer [16][17] activities. The use of the Ugi reaction followed by post-cyclization is an effective strategy that yields diverse heterocycle-containing peptidomimetics and requires a minimal number of steps [18]. For example, Mazur et al. [19] developed an efficient method

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

• linker provides entry to 1,2,3,6-tetrahydropyridines. Additionally, in the absence of internal nucleophiles, this methodology yields aryl-substituted 1,3-dienes. This work introduces a palladium-free, single-step alternative to multistep heterocycle construction from propargylsilanes and highlights the

Enantioselective desymmetrization strategy of prochiral 1,3-diols in natural product synthesis

• Lihua Wei,
• Rui Yang,
• Zhifeng Shi and
• Zhiqiang Ma

Beilstein J. Org. Chem. 2025, 21, 1932–1963, doi:10.3762/bjoc.21.151

• JohnPhos (6) induced cyclization, yielding bicyclic compound 7 with a 7-membered heterocycle. Final deprotection of the methoxymethyl (MOM) group in 7 afforded (+)-heliannuol D (8). Having successfully applied PPL-catalyzed acetylation to the synthesis of (+)-heliannuol D, the Shishido group subsequently

Chiral phosphoric acid-catalyzed asymmetric synthesis of helically chiral, planarly chiral and inherently chiral molecules

• Wei Liu and
• Xiaoyu Yang

Beilstein J. Org. Chem. 2025, 21, 1864–1889, doi:10.3762/bjoc.21.145

• the efficient asymmetric synthesis of inherently chiral eight-membered N-heterocycle 6,7-diphenyldibenzo[e,g][1,4]diazocines (DDDs), which displayed a rigid saddle-shaped configuration [16]. Starting from readily available [1,1'-biphenyl]-2,2'-diamines 62 and benzyl compounds 63, the asymmetric

• CPA-catalyzed cyclization of INT-E through the dual hydrogen bonding activation transition state TS-1 afforded the eight-membered heterocycle INT-F with a stereogenic center. Through the elimination of aniline 73, the saddle-shaped dibenzo[1,5]diazocine 72 was produced via a central-to-inherent

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

• nitrogen in “ortho” position (according to the nomenclature in the original paper) [14] also gives slightly twisted Z-isomers 10a and 10b. Moreover, a rough approximation of the thermal lifetime could be made considering the nature and connectivity of the heterocycle as either “complete” or “partial

• lifetimes with great accuracy [7]. In summary, the more extended the conjugation of the heterocycle with the N=N bond, the more feasible the inversion mechanism (which does not involve the rupture of the double N=N bond). The less conjugated switches, however, would undergo rotation around the (instant

[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

• 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

• a single diastereomer with traces or no of the other one (dr >19:1). For the derivative 5e with an oxygen-containing heterocycle, we failed to obtain the corresponding products under any of the proposed conditions. In all cases, we observed only very complex mixtures with traces of the target

• reaction is shown to proceed with exclusive formation of a single diastereomer of the spirocyclic product, the exact configuration of which is dependent on the nature of heterocycle employed. Key stereo- and electronic factors for successful realization of the cycliaddition reaction were discovered, which

Catalytic asymmetric reactions of isocyanides for constructing non-central chirality

• Jia-Yu Liao

Beilstein J. Org. Chem. 2025, 21, 1648–1660, doi:10.3762/bjoc.21.129

• nucleophiles in the DKR of various bridged biaryls bearing different linkages to give diverse nitrogen heterocycle-substituted atropoisomeric biaryls. In 2021, our group achieved the catalytic enantioselective DKR of biaryl lactones 46 with α-acidic isocyanides (Scheme 8a) [48]. By using Ag2CO3 and cinchonine

Facile synthesis of hydantoin/1,2,4-oxadiazoline spiro-compounds via 1,3-dipolar cycloaddition of nitrile oxides to 5-iminohydantoins

• Juliana V. Petrova,
• Varvara T. Tkachenko,
• Victor A. Tafeenko,
• Anna S. Pestretsova,
• Vadim S. Pokrovsky,
• Maxim E. Kukushkin and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2025, 21, 1552–1560, doi:10.3762/bjoc.21.118

• therapeutic efficacy (lower IC50 values) [18] but greater toxicity to healthy cells in comparison with spiro compounds [19]. Such hybrid-designed molecules may contain a third heterocycle as a linker, spiro-joined with one of the pharmacophore moieties. In this case, another pharmacophore fragment is included

Highly distinguishable isomeric states of a tripodal arylazopyrazole derivative on graphite through electron/hole-induced switching at ambient conditions

• Himani Malik,
• Sudha Devi,
• Debapriya Gupta,
• Ankit Kumar Gaur,
• Sugumar Venkataramani and
• Thiruvancheril G. Gopakumar

Beilstein J. Org. Chem. 2025, 21, 1496–1507, doi:10.3762/bjoc.21.112

• derivatives play a crucial role in realizing efficient bidirectional photoswitches with longer half-lives [18][19]. In particular, replacing one of the phenyl units in AB with a five-membered heterocycle and the resulting Z isomer of phenylazoheteroarenes has extended half-life ranging up to 1000 days and

Advances in nitrogen-containing helicenes: synthesis, chiroptical properties, and optoelectronic applications

• Meng Qiu,
• Jing Du,
• Nai-Te Yao,
• Xin-Yue Wang and
• Han-Yuan Gong

Beilstein J. Org. Chem. 2025, 21, 1422–1453, doi:10.3762/bjoc.21.106

• , and 60c – featuring 2,1,3-thiadiazole termini [75] (Table 20). Among them, compound 60c exhibited pronounced CPL activity in toluene (|glum| = 0.04, ΦF = 3%), demonstrating the efficacy of terminal heterocycle incorporation for boosting chiroptical performance. In 2024, Babu and co-workers developed