Chitosan-supported CuI-catalyzed cascade reaction of 2-halobenzoic acids and amidines for the synthesis of quinazolinones

• Xuhong Zhao,
• Weishuang Li,
• Mengli Yang,
• Bojie Li,
• Yaoyao Zhang,
• Lizhen Huang and
• Lei Zhu

Beilstein J. Org. Chem. 2025, 21, 839–844, doi:10.3762/bjoc.21.67

• ], but can also be readily converted into other functional compounds under specific conditions [4][5]. Due to their significant biological relevance and potential applications, numerous synthetic methods have been recently developed to synthesize these useful intermediates [6][7][8][9]. Among these

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

• intermediates in the synthesis of 2-pyrrolidinone ring containing bioactive medicinal compounds [18]. In this article, we report the accidental synthesis of 4-(1-methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-dione derivatives via the transimination reaction between 4-[1-(4-methoxybenzyl)amino

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

• intermediates in total [29][30] and bio-synthesis protocols [31], e.g., in inositol chemistry [32] or towards aminocyclitols [33]. The potential of these compounds as functional photoswitches was primarily assessed in the 1960s and 1970s by Prinzbach and co-workers, who identified a variety of rearrangement

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

• -system configuration promotes selective functionalization, enabling the synthesis of various complex products through a single transformation [17][18][19]. Therefore, allenes have become versatile intermediates in numerous transition-metal-catalyzed reactions [20][21]. Despite extensive studies on the

Recent advances in the electrochemical synthesis of organophosphorus compounds

• Babak Kaboudin,
• Milad Behroozi,
• Sepideh Sadighi and
• Fatemeh Asgharzadeh

Beilstein J. Org. Chem. 2025, 21, 770–797, doi:10.3762/bjoc.21.61

• efficiency of reactions [14][15][16][17][18][19][20][21]. Organophosphorous compounds are essential materials with broad applications in medicinal chemistry, synthesis, agriculture, as ligands, and intermediates to prepare complex compounds. Due to their importance, scientists have introduced many studies in

• can lead to lower reaction yields because various reaction pathways, including those involving unstable metal-organic intermediates, may become involved. Cyclic voltammetry analysis in both solution and solid phases, using a carbon paste electrode (CPE), revealed that the nature of the bridging ligand

• phosphorus-centered radical intermediates was confirmed. The importance of Cp2Fe and the amount of diphenylphosphine oxide became evident when a significant decrease in reaction yield was observed both in the absence of Cp2Fe (Table 5) and when a lower amount of diphenylphosphine oxide was used. Both

Development and mechanistic studies of calcium–BINOL phosphate-catalyzed hydrocyanation of hydrazones

• Carola Tortora,
• Christian A. Fischer,
• Sascha Kohlbauer,
• Alexandru Zamfir,
• Gerd M. Ballmann,
• Jürgen Pahl,
• Sjoerd Harder and
• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2025, 21, 755–765, doi:10.3762/bjoc.21.59

• provides (together with the similarly exothermic complexation of calcium complex 7 with hydrazone) driving force for the catalytic cycle, but, on the other hand, may impede enantioselectivity, because of a "backwater" effect equaling out outcomes from different reaction pathways before intermediates are

Copper-catalyzed domino cyclization of anilines and cyclobutanone oxime: a scalable and versatile route to spirotetrahydroquinoline derivatives

• Qingqing Jiang,
• Xinyi Lei,
• Pan Gao and
• Yu Yuan

Beilstein J. Org. Chem. 2025, 21, 749–754, doi:10.3762/bjoc.21.58

• to generate an enamine intermediate. Subsequently, an intermolecular cyclization occurs between the enamine and imine intermediates, ultimately yielding the final target product through an aromatization process (Scheme 4). Conclusion In summary, we have developed an efficient and practical copper

• intermediates, followed by intermolecular cyclization and aromatization. The scalability of this method was demonstrated through a gram-scale reaction, highlighting its potential for practical applications in medicinal chemistry and drug discovery. Synthetic strategies for the construction of

Recent advances in allylation of chiral secondary alkylcopper species

• Minjae Kim,
• Gwanggyun Kim,
• Doyoon Kim,
• Jun Hee Lee and
• Seung Hwan Cho

Beilstein J. Org. Chem. 2025, 21, 639–658, doi:10.3762/bjoc.21.51

• generation of chiral secondary alkylcopper species has been a significant challenge in organic synthesis, primarily due to their inherent instability and tendency to racemization [38]. For generating the key chiral organocopper intermediates, two distinct approaches have been developed: one utilizing chiral

• stereochemical integrity. Through these careful experimental controls, Knochel and co-workers effectively addressed the long-standing challenge of handling these traditionally unstable chiral organometallic intermediates. Copper-catalyzed stereospecific coupling of chiral organoboron species with allylic

• has been challenging due to the tendency of α-CF3-substituted alkylcopper intermediates 39 to undergo undesired β-F elimination (Scheme 14a) [54]. In 2021, Hirano and co-workers made a significant advance in this area by disclosing a copper-catalyzed regio- and enantioselective hydroallylation of 1

Photocatalyzed elaboration of antibody-based bioconjugates

• Marine Le Stum,
• Eugénie Romero and
• Gary A. Molander

Beilstein J. Org. Chem. 2025, 21, 616–629, doi:10.3762/bjoc.21.49

• thus to have a better control of the selectivity and the DAR, leading to more homogeneous ADCs. In this specific context, photocatalysis (Figure 2) enables site-specific bioconjugation by generating reactive intermediates (such as radicals or electron-deficient species) that can selectively react under

• emerged as a transformative approach in the modification of proteins, enabling researchers to achieve selective and efficient conjugation under mild conditions [37]. By utilizing visible light and transition-metal catalysts, this technique allows the generation of reactive intermediates that can

• intermediates can lead to protein denaturation or aggregation [61]. Because photoredox reactions often generate highly reactive species (such as radicals or singlet oxygen), long exposure times could cause unwanted side reactions, including the degradation of 3D structure of the protein or antibody. A short

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

• for the formation of intermediates. Gao et al. studied the generation of metal acetylide A by IR spectroscopy [65]. When subsequent additions of 1 equiv FeCl3 were made in a solution of alkyne and TMG, the C–H stretch peak at 3277 cm−1 started to decrease as the temperature increased from 30 to 100 °C

Synthesis of electrophile-tethered preQ₁ analogs for covalent attachment to preQ₁ RNA

• Laurin Flemmich and
• Ronald Micura

Beilstein J. Org. Chem. 2025, 21, 483–489, doi:10.3762/bjoc.21.35

• such reactive preQ1 and (2,6-diamino-7-aminomethyl-7-deazapurine) DPQ1 ligands. The readily accessible key intermediates of preQ0 and DPQ0 (both bearing a nitrile moiety instead of the aminomethyl group) were reduced to the corresponding 7-formyl-7-deazapurine counterparts. These readily undergo

Photomechanochemistry: harnessing mechanical forces to enhance photochemical reactions

• Francesco Mele,
• Ana M. Constantin,
• Andrea Porcheddu,
• Raimondo Maggi,
• Giovanni Maestri,
• Nicola Della Ca’ and
• Luca Capaldo

Beilstein J. Org. Chem. 2025, 21, 458–472, doi:10.3762/bjoc.21.33

• mechanistic scenario than that operating in solution [71], where photogenerated thiyl radicals proved crucial intermediates. Parallelly, Hernández reported a photomechanochemical approach for the borylation of aryldiazonium salts in a ball milling apparatus equipped with a transparent polymethylmethacrylate

Electrochemical synthesis of cyclic biaryl λ³-bromanes from 2,2’-dibromobiphenyls

• Andrejs Savkins and
• Igors Sokolovs

Beilstein J. Org. Chem. 2025, 21, 451–457, doi:10.3762/bjoc.21.32

• molecular nitrogen in diazonium compounds. Accordingly, pre-formed [12] or in situ-generated 2,2’-bromodiazonium salts 2 [11][13][14] furnish cyclic bromine(III) species 1 under thermal decomposition conditions (Scheme 1, reaction 1). The diazonium intermediates 2 are obtained by diazotation of 2'-bromo

• -[1,1'-biphenyl]-2-amines 3 with sodium nitrite and an acid under aqueous conditions. Recently, Wencel-Delord and co-workers disclosed an improved protocol toward diazonium intermediates 2 under non-aqueous conditions (t-BuONO and MsOH in acetonitrile) [4]. Nevertheless, the improved method still

Identification and removal of a cryptic impurity in pomalidomide-PEG based PROTAC

• Bingnan Wang,
• Yong Lu and
• Chuo Chen

Beilstein J. Org. Chem. 2025, 21, 407–411, doi:10.3762/bjoc.21.28

• pomalidomide or its close analogs, indicating that a side reaction unrelated to the SNAr of the fluoride has occurred. 1H NMR and MS analyses suggested that phthalimide 5 was the byproduct formed through this series of transformations. Supporting this hypothesis, analysis of the reaction intermediates

The effect of neighbouring group participation and possible long range remote group participation in O-glycosylation

• Rituparna Das and
• Balaram Mukhopadhyay

Beilstein J. Org. Chem. 2025, 21, 369–406, doi:10.3762/bjoc.21.27

• supported by NMR data showing the formation of the respective intermediates. Previously, this stabilisation of a similar α-glycosyl intermediate had been successfully implemented by Crich et al. leading to high β-selectivity in challenging mannose and rhamnose moieties [37]. The moderate yield and β

• corresponding orthophosphate intermediates. However, the NMR analysis showed the formation of covalent α-glycosyl triflates 72 as the intermediate indicating an SN2-like mechanistic pathway where the acceptor attacked from the opposite face of the α-triflate intermediates (path A, Scheme 13) which was triggered

• intermediates [144]. However, C-2 phthalimidoxy-protected trichloroacetimidate glycosyl donors gave higher 1,2-trans selectivity in comparison to C-2 phthalimidoxy-protected N-phenyl 2,2,2-trifluoroacetimidate glycosyl donors. Ether-type participating protecting groups: In the absence of neighbouring acyl-type

Synthesis, structure, ionochromic and cytotoxic properties of new 2-(indolin-2-yl)-1,3-tropolones

• Yurii A. Sayapin,
• Eugeny A. Gusakov,
• Inna O. Tupaeva,
• Alexander D. Dubonosov,
• Igor V. Dorogan,
• Valery V. Tkachev,
• Anna S. Goncharova,
• Gennady V. Shilov,
• Natalia S. Kuznetsova,
• Svetlana Y. Filippova,
• Tatyana A. Krasnikova,
• Yanis A. Boumber,
• Alexey Y. Maksimov,
• Sergey M. Aldoshin and
• Vladimir I. Minkin

Beilstein J. Org. Chem. 2025, 21, 358–368, doi:10.3762/bjoc.21.26

• ). As shown in Scheme 2, in the initial step, the aldol condensation of 2,3,3-trimethylindolenine 2 with o-chloranil (3) leads to the intermediate compounds, 6-(2-hetarylmethylene)-6-hydroxy-2,4-cyclohexadien-1-ones 4. Such intermediates were isolated preparatively and structurally characterized in the

Three-component reactions of conjugated dienes, CH acids and formaldehyde under diffusion mixing conditions

• Dmitry E. Shybanov,
• Maxim E. Kukushkin,
• Eugene V. Babaev,
• Nikolai V. Zyk and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2025, 21, 262–269, doi:10.3762/bjoc.21.18

• generate crotonic condensation adducts of active methylene compounds and formaldehyde at room temperature in the absence of strong acids and bases. The formed adducts were highly reactive intermediates capable of reacting with dienes in a three-component reaction, leading to the formation of Diels–Alder

• placed an open small vial with a solution of the other starting compounds (Figure 1). During the reaction, formaldehyde vapors from the outer vial were slowly absorbed by the mixture in the inner vial, which ensured an extremely low concentration of CH2O and intermediates in the reaction. An alternative

• to the diffusion mixing method is the slow dropwise addition of a reagent to the reaction mixture. However, in the latter case it is not possible to achieve uniform generation of active intermediates due to their formation in a local area, which accelerates unwanted side processes [19]. The results

Synthesis of disulfides and 3-sulfenylchromones from sodium sulfinates catalyzed by TBAI

• Zhenlei Zhang,
• Ying Wang,
• Xingxing Pan,
• Manqi Zhang,
• Wei Zhao,
• Meng Li and
• Hao Zhang

Beilstein J. Org. Chem. 2025, 21, 253–261, doi:10.3762/bjoc.21.17

• alkylsulfinates were also successfully converted to the corresponding disulfides in high yields (2n and 2o). In our synthesis of disulfides, thiosulfonates were also present as intermediates besides forming disulfides. In view of the fact that in the literature above disulfides or thiosulfonates could be

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

• Synthesis of primary amides via the generation of copper–imidate radical intermediates In a subsequent study, the research group of Son developed a method for the reduction of dioxazolones to synthesize primary amides under mild reducing conditions in copper catalysis (Scheme 10) [103]. The reaction was

• –N, P–N, and N–H bond-forming reactions. Several studies have proposed copper nitrenoid intermediates originating from dioxazolones, involving an N-acyl nitrene transfer or hydrogen atom transfer process, representing creative synthetic solutions that were previously unachievable using conventional

• approaches. Despite the synthetic strategies to generate the copper nitrenoid intermediates are gaining more attention [104][105], several limitations still remain. First, multiple steps are required to prepare dioxazolones, synthesized conventionally from carboxylic acids or acid chlorides over two steps

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

• reactions, particularly in controlling the high reactivity and selectivity of radical intermediates [13][14]. Early studies on copper-mediated radical reactions, such as Julia’s work on radical cyclization reaction [15], along with advancements in dimerization [16][17], oxidative cleavage [18][19], and

• viable alternatives to conventional chemical oxidizing and reducing agents [31], electrochemical reactions not only enable substrates to undergo single-electron transfer at the cathode or anode, either directly or indirectly, generating highly reactive radical intermediates, but also allow direct

• alkylamines with arylboronic acids, achieving high yields. Mechanistic studies revealed that the mediator plays multiple roles, including rapidly oxidizing low-valent Cu intermediates to maintain high Cu(II) concentrations, removing Cu metal from the cathode to regenerate the active Cu catalyst, revealing the

Nickel-catalyzed cross-coupling of 2-fluorobenzofurans with arylboronic acids via aromatic C–F bond activation

• Takeshi Fujita,
• Haruna Yabuki,
• Ryutaro Morioka,
• Kohei Fuchibe and
• Junji Ichikawa

Beilstein J. Org. Chem. 2025, 21, 146–154, doi:10.3762/bjoc.21.8

• -(trifluoromethyl)-1-alkenes strongly interact with electron-rich zero-valent nickel species to form nickelacyclopropanes C [15][16][17]. These intermediates enable C–F bond activation through the formation of nickelacyclopentenes D with alkynes, followed by β-fluorine elimination, leading to defluorinative

• -deficient carbon atom owing to the nearby fluorine and oxygen atoms. We expected that 2-fluorobenzofurans 1 could form nickelacyclopropanes E upon treatment with zero-valent nickel species. Subsequent β-fluorine elimination from these intermediates E would facilitate the activation of aromatic C–F bonds

• (Scheme 1c). In this study, we demonstrate nickel-catalyzed defluorinative cross-coupling [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] of 2-fluorobenzofurans 1 with arylboronic acids 2 at ambient temperature, with nickelacyclopropanes E serving as crucial intermediates for the

Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• reaction proceeds through an initial single-electron transfer from NFBS assisted by the active copper species, followed by intermolecular hydrogen-atom transfer from the carbazate. The nitrogen radical intermediate I thus formed is decomposed into the acyl or alkyl radical intermediates II and III

• additive. Some control experiments support a mechanism whose key intermediates are the formation of the iminium ion XIX, originated from aniline with formaldehyde which serves as the C1 building block, and the generation of the cyclic α,β-unsaturated ethers XX by Cu(OTf)2-catalyzed dehydrogenation of the

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

• enantioselectivities (Scheme 13). Axially chiral compounds with an N–N stereogenic axis can be synthesized by an NHC-catalyzed (3 + 3) annulation [33]. The key feature of this transformation is the cycloaddition of α,β-unsaturated azolium intermediates with thioureas. In this way, a range of diversely substituted N–N

• -Breslow-type intermediates with the chiral NHC-catalyst and subsequent deprotonation toward the nitrile product. Zhang, Wang, Ye, and co-workers utilized NHC-catalysis for the atroposelective synthesis of axially chiral diaryl ethers 59 and 61 [38]. This transformation was realized via desymmetrization of

Emerging trends in the optimization of organic synthesis through high-throughput tools and machine learning

• Pablo Quijano Velasco,
• Kedar Hippalgaonkar and
• Balamurugan Ramalingam

Beilstein J. Org. Chem. 2025, 21, 10–38, doi:10.3762/bjoc.21.3

• intermediates. A detailed discussion on the optimization strategy is described in the section Machine-learning-driven optimization of chemical reactions. Robochem, a HTE platform, was designed to streamline the screening of photochemical reactions, facilitating the rapid generation of diverse reaction mixtures

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

• 5aa (Table 1, entry 2) but with prior degassed solvent (DMF), to prevent potential oxidation of the sulfenate to sulfinate anions. Indeed, the oxidation of the unstable sulfenate intermediates has been previously reported by Waser when using EBX – an HIR applied in the transfer of alkynes to sulfenate