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

• tertiary enamides as cyclization precursors (Scheme 6). The analogous polycyclization generated a tetracyclic N-heterocycle with three continuous stereogenic centers, one of them being an aza-quaternary carbon [31]. The resulting fused ring-system structurally resembles the nucleus of erysotramidine

• notable example is (−)-cephalocyclidin A, a cytotoxic pentacyclic cephalotaxus alkaloid [33][34]. Although the molecular structure contains a benzo-bridge ring system, disconnection of this bridge reveals a critical tricyclic N-heterocycle. To efficiently synthesize this tricycle, polycyclization of

Substituent effects in N-acetylated phenylazopyrazole photoswitches

• Radek Tovtik,
• Dennis Marzin,
• Pia Weigel,
• Stefano Crespi and
• Nadja A. Simeth

Beilstein J. Org. Chem. 2025, 21, 830–838, doi:10.3762/bjoc.21.66

• often show higher quantum yields and increased thermal half-life of the metastable state. For the half-life, the choice of the heterocycle is crucial, as revealed through density functional theory (DFT) calculations, which showed that a 5-membered ring promotes the stability of the Z isomer [30]. Within

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

• including protein kinase A (PKA). Fluorination was investigated as a strategy for altering the conformation of the central seven-membered nitrogen heterocycle, and hence possibly improving the selectivity for PKCε. A variety of fluorination patterns were investigated (100–103, Figure 11), which were found

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

• , replacement of graphite with stainless steel (SS) [9] as the cathode material afforded similar yields of the desired heterocycle 6a (72% and 70%, respectively; Table 1, entries 8 and 10), so both graphite and SS were subsequently used in the scope studies (vide infra). Other cathode materials such as Pt or

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

• (as exemplified in Scheme 10 above) and its use in heterocycle multicomponent synthesis is not limited to quinolines, as the reaction to diarylpyridines [42][43], quinazolinones [44], and pyrazoles [45] is also described by this approach (Scheme 11). These examples deserve further discussion

• reaction works very well for a wide variety of functional groups and substitution patterns in the aryl methyl ketone substrate, affording the desired heterocycle with good yields. Even heteroaryl methyl ketone and 1,3-dicarbonyl compounds work very well under these reaction conditions, leading to more

• complex heterocycle products of general structure 9 and 11. Interestingly, Wu et al. demonstrated that the reaction did not proceed when paraformaldehyde is used as the C1 synthon, indicating that formaldehyde is not involved in the reaction [43]. Furthermore, in isotope labelling studies using DMSO-d6

Vinylogous functionalization of 4-alkylidene-5-aminopyrazoles with methyl trifluoropyruvates

• Judit Hostalet-Romero,
• Laura Carceller-Ferrer,
• Gonzalo Blay,
• Amparo Sanz-Marco,
• José R. Pedro and
• Carlos Vila

Beilstein J. Org. Chem. 2025, 21, 533–540, doi:10.3762/bjoc.21.41

• compounds that generally enhance the bioactivity of agrochemical and pharmaceutical substrates. On the other hand, 5-aminopyrazole [11][12] is a nitrogen heterocycle that has attracted significant interest to pharmaceutical and medicinal chemists due to the presence of this nitrogen heterocycle in various

• on the regioselective electrophilic functionalization of this nitrogen heterocycle [15][16][17][18][19][20][21][22][23][24][25]. However, the vinylogous functionalization of 5-aminopyrazoles has not been described to the best of our knowledge (Figure 2). As a part of our ongoing interest in the

• ] as electrophiles. It is noteworthy that the development of such vinylogous functionalizations of this nitrogen heterocycle with a fluorine-containing electrophile may be of interest to pharmaceutical and medicinal chemists. Results and Discussion 4-(Alkenyl)-5-aminopyrazoles 3 were selected as

Unraveling aromaticity: the dual worlds of pyrazole, pyrazoline, and 3D carborane

• Zahra Noori,
• Miquel Solà,
• Clara Viñas,
• Francesc Teixidor and
• Jordi Poater

Beilstein J. Org. Chem. 2025, 21, 412–420, doi:10.3762/bjoc.21.29

• cage retains its aromatic character, the pyrazole’s aromaticity is lost. As a result, rather than forming o-carborane-fused pyrazoles, the synthesis yielded o-carborane-fused pyrazolines, which are non-aromatic. The limited overlap between the π molecular orbitals (MOs) of the planar heterocycle and

• carborane and the π-aromaticity of the heterocycle are orthogonal, making a true 3D/2D aromatic system unachievable. The carborane is highly aromatic, generating highly negative NICS values (−25 to −30 ppm). We have observed that these high NICS values extend to fused rings, leading to incorrect estimations

• compared to the C–C bond by 2.4 kcal/mol further supports the above statement [44]. Next, we have compared the above o-carborane-fused pyrazoles with a series of reference systems with the aim to better understand the electronic structure of the fused heterocycle and its aromaticity (Figure 3). First, the

Synthesis of acenaphthylene-fused heteroarenes and polyoxygenated benzo[j]fluoranthenes via a Pd-catalyzed Suzuki–Miyaura/C–H arylation cascade

• Merve Yence,
• Dilgam Ahmadli,
• Damla Surmeli,
• Umut Mert Karacaoğlu,
• Sujit Pal and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2024, 20, 3290–3298, doi:10.3762/bjoc.20.273

• , entries 5 and 6). As aforementioned, in our previous work, we had reported the use of 4-pyridylboronic acid as the only heterocycle in our fluoranthene synthesis methodology, and azafluoranthene 15h was obtained in that study as the only possible regioisomer [43]. In the current work, we opted to check

Reactivity of hypervalent iodine(III) reagents bearing a benzylamine with sulfenate salts

• Beatriz Dedeiras,
• Catarina S. Caldeira,
• José C. Cunha,
• Clara S. B. Gomes and
• M. Manuel B. Marques

Beilstein J. Org. Chem. 2024, 20, 3281–3289, doi:10.3762/bjoc.20.272

• ]; (ii) the incorporation of the iodine atom in the 5-membered heterocycle [10]; and (iii) the trans effect, due to the interaction of the hypervalent bonds established by the axial ligands, where iodine orbitals are shared with both heteroatoms [11]. As a result, benziodoxol(on)es have found application

Intramolecular C–H arylation of pyridine derivatives with a palladium catalyst for the synthesis of multiply fused heteroaromatic compounds

• Yuki Nakanishi,
• Shoichi Sugita,
• Kentaro Okano and
• Atsunori Mori

Beilstein J. Org. Chem. 2024, 20, 3256–3262, doi:10.3762/bjoc.20.269

• efficiencies in atom economy [3][4]. The extension of the reaction to an intramolecular version represents a viable approach for the construction of several fused-ring skeletons [5]. Such ring structures containing heterocyclic rings would be of crucial importance because heterocycle-fused ring structures [6

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

• build the principal heterocycle of the compounds. Good reaction yields (70–87%) made it possible to obtain the aminothiophene carboxylates necessary for the following steps of the route [52]. Some of the intermediates of the Gewald reaction were oxidized to provide further exploration of the

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

• this review aims to fill. The synthetic uses of HVI reagents [14][15][16], their involvement in heterocycle synthesis [17][18][19], and alkene functionalisation [20][21], have each been well-reviewed elsewhere. Review Hypervalent iodine-mediated fluorocyclisation Fluorine can substantially improve the

• . The authors proposed two possible mechanisms for the reaction (Scheme 24). Firstly, a chloronium ion is generated by HVI and LiCl followed by intramolecular nucleophilic attack by nitrogen to form the heterocycle. Secondly, oxidation of the unsaturated guanidine forms an intermediate aziridinium A

Tunable full-color dual-state (solution and solid) emission of push–pull molecules containing the 1-pyrindane moiety

• Anastasia I. Ershova,
• Sergey V. Fedoseev,
• Konstantin V. Lipin,
• Mikhail Yu. Ievlev,
• Oleg E. Nasakin and
• Oleg V. Ershov

Beilstein J. Org. Chem. 2024, 20, 3016–3025, doi:10.3762/bjoc.20.251

• rigidity along the C–C bond between the heterocycle and ethene bridge due to the fused cyclic fragment. As a consequence of the additional ring, the fluorescence efficiency increased. At the same time, solid-state emission was observed due to the steric hindrance, which prevented intermolecular

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

• this Li and Jiang, created an effective ball-milling process for the N-arylation of amines 38 with the assistance of diaryliodonium salts 16 (Scheme 15) [67]. The arylation of an amino group or nitrogen heterocycle occurred effectively when the reaction is performed under solvent-free conditions or

C–C Coupling in sterically demanding porphyrin environments

• Liam Cribbin,
• Brendan Twamley,
• Nicolae Buga,
• John E. O’ Brien,
• Raphael Bühler,
• Roland A. Fischer and
• Mathias O. Senge

Beilstein J. Org. Chem. 2024, 20, 2784–2798, doi:10.3762/bjoc.20.234

• [48], switching catalyst to Pd(PPh)3, and base to Na2CO3 (Table 1, entry 16) gave no product. Ultimately, an increased catalyst loading of 25 mol % per C–Br bond gave the desired porphyrin in a 16% yield when using Cs2CO3 as base. The synthesis of other heterocycle-appended dodecasubstituted

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

• established for these compounds. The electrochemical behavior of the studied compounds is influenced by several factors: the nature of the heterocycle and its substituents, the presence of a sulfur atom in the catechol ring, or a thione group in the heterocyclic core. The radical scavenging activity and

• possibility of alkylation of the nitrogen atom in the heterocycle cannot be excluded. This alternative pathway is similar to the previously described interaction of the aforementioned catechol with 3,5-dimethylpyrazole or benzimidazole [55]. A study of the structure, electrochemical properties, anti

• ). At the same time, the interaction of 2-mercapto-substituted derivatives of 1,3,4-oxadiazole or 1,2,4-triazole with the starting catechol proceeds at the nitrogen atom of the five-membered heterocycle due to the possibility of the thione–thiol tautomerism in the starting thiol [26][27]. Consequently

Tandem diazotization/cyclization approach for the synthesis of a fused 1,2,3-triazinone-furazan/furoxan heterocyclic system

• Yuri A. Sidunets,
• Valeriya G. Melekhina and
• Leonid L. Fershtat

Beilstein J. Org. Chem. 2024, 20, 2342–2348, doi:10.3762/bjoc.20.200

• coupling reactions of the obtained compounds 2. It should be emphasized that amino-1,2,5-oxadiazoles correspond to very weak nucleophiles due to the highly electron-withdrawing effect of the heterocycle. Our previous efforts achieved a certain result indicating that (1,2,5-oxadiazolyl)diazonium salts

• , indicating that the developed tandem protocol does not depend on the presence of the N-oxide moiety in the parent heterocycle. All synthesized triazinones 1 and 7 were fully characterized by IR, 1H and 13C NMR spectroscopy, and high-resolution mass spectrometry. The structure of compounds 1b and 7h was

Heterocycle-guided synthesis of m-hetarylanilines via three-component benzannulation

• Andrey R. Galeev,
• Maksim V. Dmitriev,
• Alexander S. Novikov and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2024, 20, 2208–2216, doi:10.3762/bjoc.20.188

• Federation Research Institute of Chemistry, Рeoples’ Friendship University of Russia (RUDN University), Miklukho-Maklaya Street, 6, Moscow, 117198, Russian Federation 10.3762/bjoc.20.188 Abstract A one-pot three-component synthesis of substituted meta-hetarylanilines from heterocycle-substituted 1,3

• desired meta-heterocycle aniline 3ag was prepared in low yield. Finally, the developed method is suitable for the late-stage arylation of drug-like molecules such as deacetyllinezolid (3ak). The meta-substituted anilines 3 are formed in a sequence of reactions shown in Scheme 6 [53]. Firstly, the reaction

Efficacy of radical reactions of isocyanides with heteroatom radicals in organic synthesis

• Akiya Ogawa and
• Yuki Yamamoto

Beilstein J. Org. Chem. 2024, 20, 2114–2128, doi:10.3762/bjoc.20.182

• reaction. At the same time, Bachi et al. succeeded in synthesizing a 5-membered nitrogen-containing heterocycle based on the 5-exo cyclization of isocyanides with alkenyl or alkynyl groups using thiols as mediators (Scheme 14) [57]. The generated thiyl radical attacks the isocyano group and forms imidoyl

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

• -acetoacetylcoumarin 41, 3-bromoacylpyran 42, and semicarbazide 40 (Scheme 12) [65]. Alternatively, the corresponding chromenes can replace the 3-bromoacylpyrans. A notable advantage of this process is its catalyst-free nature and the achievement of good regioselectivity. Due to the high heterocycle density, this

• reactions in heterocycle synthesis [163][164] and certainly also for substituted pyrazoles. Four classes of 1,3-dipoles are considered as synthetic equivalents for the CN2 synthon: diazo compounds [165], nitrilimines [166], sydnones [167], and azomethinimines [168]. These intermediates undergo (3 + 2

Harnessing the versatility of hydrazones through electrosynthetic oxidative transformations

• Aurélie Claraz

Beilstein J. Org. Chem. 2024, 20, 1988–2004, doi:10.3762/bjoc.20.175

• access to diazo compounds as either synthetic intermediates or products. A special attention is paid to the reaction mechanism with the aim to encourage further development in this field. Keywords: C–H functionalization; diazo compound; electrosynthesis; hydrazone; nitrogen-containing heterocycle

• hydrazones initiated with the SET anodic oxidation of the hydrazone and deprotonation to form the N-centered radical 10. After aza-cyclization on the aromatic ring, a second SET oxidation and deprotonation delivered the heterocycle 9. This mechanism was supported by cyclic voltammetry analysis of a model

• point of view, the authors proposed the formation of N-pyridyl radical 18 through the anodic oxidation of in situ-generated anion 17. Subsequent radical cyclization, second anodic cyclization and deprotonation yielded the fused heterocycle 16. Similarly, Youssef and Alajimi disclosed the electrochemical

Regioselective alkylation of a versatile indazole: Electrophile scope and mechanistic insights from density functional theory calculations

• Pengcheng Lu,
• Luis Juarez,
• Paul A. Wiget,
• Weihe Zhang,
• Krishnan Raman and
• Pravin L. Kotian

Beilstein J. Org. Chem. 2024, 20, 1940–1954, doi:10.3762/bjoc.20.170

• indazoles would provide greater synthetic utility for this valuable heterocycle. These examples suggest a common intermediate such as methyl 5-bromo-1H-indazole-3-carboxylate (6) could be used to generate such compounds. An alkylation strategy that uses the vast array of commercially available alcohols as

Novel oxidative routes to N-arylpyridoindazolium salts

• Oleg A. Levitskiy,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2024, 20, 1906–1913, doi:10.3762/bjoc.20.166

• electrode in MeCN solution using Bu4NBF4 as a supporting electrolyte. Oxidation of the salts occurs at high positive potentials (>2 V vs Ag/AgCl, KCl(sat.), Figure 1a), in accordance with the cationic nature of the heterocycle. In the negative potential range, an irreversible peak can be observed in the

Access to 2-oxoazetidine-3-carboxylic acid derivatives via thermal microwave-assisted Wolff rearrangement of 3-diazotetramic acids in the presence of nucleophiles

• Ivan Lyutin,
• Vasilisa Krivovicheva,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 1894–1899, doi:10.3762/bjoc.20.164

• (azetidin-2-one) scaffold to medicinal chemistry and drug design is self-evident. This four-membered heterocycle is a key fragment of many antibiotics [1], including penicillin and its analogues, as well as other pharmacologically important molecules [2]. Therefore, the search for new efficient and

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162