Rhodium-catalysed connective synthesis of diverse reactive probes bearing S(VI) electrophilic warheads

• Scott Rice,
• Julian Chesti,
• William R. T. Mosedale,
• Megan H. Wright,
• Stephen P. Marsden,
• Terry K. Smith and
• Adam Nelson

Beilstein J. Org. Chem. 2025, 21, 1924–1931, doi:10.3762/bjoc.21.150

• ][3]. Established sets of reactive probes are typically armed with electrophilic warheads that have the potential to target nucleophilic amino acid side chains. Most reactive probe sets bear cysteine-directed warheads [3][4][5][6][7], although sets have also been designed to target a wider range of

• that all of these active compounds are 4-phenylpiperidinyl amides derived from the same α-diazoamide 2, suggesting that this feature is important for activity. Conclusion We have developed a connective synthesis of reactive probes bearing S(VI) electrophilic warheads. Each probe was prepared by rhodium

• ) electrophilic warheads (WH). Diverse probes 3 might be accessible by functionalising α-diazoamide substrates 2 via alternative reaction modes. Structures and reactions of co-substrates. Panel A: structures of the 16 selected co-substrates C1–16, together with two additional co-substrates C17 and C18 that were

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

• through a [3 + 3]-cycloaddition reaction. By employing the CPA-catalyzed asymmetric electrophilic amination reaction with azodicarboxylate on the phenol moiety, efficient kinetic resolution of 25 proceeded to yield both the amination products 26 and the recovered starting material with high

• electrophilic amination reaction of the aniline moiety with azodicarboxylates [37][38], the introduction of a bulky hydrazine group restricted the free flipping of the benzene ring, leading to the formation of planar chiral macrocycle 33 with high enantioselectivity (Scheme 9). Substrate scope studies

• directly used as a planarly chiral primary amine catalyst in the asymmetric electrophilic amination reaction of aldehyde 34, which yielded the α-amination product 35 with high enantioselectivity. In 2022, our group disclosed an enantioselective macrocyclization protocol for the asymmetric synthesis of

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

• corresponding imines I and I′, as supported by the detection of imine I during GC–MS analysis. Both imines coordinate with the Lewis acid FeIII forming intermediates II and II′ with enhanced electrophilicity, respectively. Another equivalent of styrene (2a) attacks the electrophilic carbon, leading to the

• formation of intermediates III and III′. Subsequent electrophilic cyclization/C–H annulation of the aromatic amine, followed by aromatization, afford intermediates V and V′. The oxidative dehydrogenation of intermediates V and V′ then results in the formation of products 3a and 3a′ and the regeneration of

Unique halogen–π association detected in single crystals of C–N atropisomeric N-(2-halophenyl)quinolin-2-one derivatives and the thione analogue

• Mai Uchibori,
• Nanami Murate,
• Kanako Shima,
• Tatsunori Sakagami,
• Ko Kanehisa,
• Gary James Richards,
• Akiko Hori and
• Osamu Kitagawa

Beilstein J. Org. Chem. 2025, 21, 1748–1756, doi:10.3762/bjoc.21.138

• classified into two major types: (1) σ-type halogen bonding, where the electrophilic region (σ-hole) of a halogen atom interacts with a lone pair on an electron-rich atom (e.g., C–X···Y), and (2) π-type halogen bonding (or halogen–π interaction), where the σ-hole interacts with an electron-rich π-system (e.g

Continuous-flow-enabled intensification in nitration processes: a review of technological developments and practical applications over the past decade

• Feng Zhou,
• Chuansong Duanmu,
• Yanxing Li,
• Jin Li,
• Haiqing Xu,
• Pan Wang and
• Kai Zhu

Beilstein J. Org. Chem. 2025, 21, 1678–1699, doi:10.3762/bjoc.21.132

• aliphatic counterparts) due to their predictable electrophilic substitution mechanisms and relatively mild reaction conditions, which enable superior controllability and regioselectivity. Unlike aromatic nitrations that predominantly follow ionic mechanisms, aliphatic systems governed by free radical

• suppressing byproduct formation from over-sulfonation and minimizing environmental burdens through reduced waste acid discharge. Water content governs the formation equilibrium of nitronium ions (NO2+), the electrophilic nitrating species, thereby dictating the overall reaction rates. In nitration processes

• dehydration. This electrophilic species subsequently engages in an aromatic electrophilic substitution, with reaction kinetics heavily influenced by the electronic nature of substituents and acid strength. Table 2 analyzes studies in the literature that utilize the flow-chemistry technology to investigate the

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

• of the resulting products in developing chiral organocatalysts was investigated as well. For instance, 28a was converted to a thiourea-tertiary amine 29 through a four-step procedure in an overall 36% yield. This compound was then utilized as the catalyst in the electrophilic amination reaction

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

• -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

Copper catalysis: a constantly evolving field

• Elena Fernández and
• Jaesook Yun

Beilstein J. Org. Chem. 2025, 21, 1477–1479, doi:10.3762/bjoc.21.109

• by Son and co-workers illustrates recent advancements in the use of dioxazolones in synthetic transformations with copper salts [4]. The authors remark that these catalytic systems, which employ dioxazolones as electrophilic amide sources, were applied for the preparation of diverse amidated products

Microwave-enhanced additive-free C–H amination of benzoxazoles catalysed by supported copper

• Andrei Paraschiv,
• Valentina Maruzzo,
• Filippo Pettazzi,
• Stefano Magliocco,
• Paolo Inaudi,
• Daria Brambilla,
• Gloria Berlier,
• Giancarlo Cravotto and
• Katia Martina

Beilstein J. Org. Chem. 2025, 21, 1462–1476, doi:10.3762/bjoc.21.108

• of azolic substrates, but here the amines and the ligands are still used in excess and auxiliary oxidants are occasionally employed [33][34][35]. Although electrophilic amines, such as chloroamines [36][37], hydroxylamine [38][39][40], acylated hydroxylamine (with a wider reaction scope) [41][42][43

• ][44] and sulfamoyl chlorides [32] can perform the coupling under basic conditions, the need for the activation of the amine as an electrophilic agent generates additional waste. This reduces atom economy and indicates lower reaction efficiency. Acid-catalysed protocols have also been specifically

Reactions of acryl thioamides with iminoiodinanes as a one-step synthesis of N-sulfonyl-2,3-dihydro-1,2-thiazoles

• Vladimir G. Ilkin,
• Pavel S. Silaichev,
• Valeriy O. Filimonov,
• Tetyana V. Beryozkina,
• Margarita D. Likhacheva,
• Pavel A. Slepukhin,
• Wim Dehaen and
• Vasiliy A. Bakulev

Beilstein J. Org. Chem. 2025, 21, 1397–1403, doi:10.3762/bjoc.21.104

• reaction did not occur. In the presence of metal catalyst PhINTs form a nitrenoid specie, containing electrophilic nitrogen. In metal-free conditions PhINTs participates in reactions as ylide with a nucleophilic nitrogen. We expected different reactivity of the two different forms of PhINTs. However, our

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

• a preparation of oxetanes via silicon-directed electrophilic cyclisation of homoallylic alcohols 49 (Scheme 12) [46]. The reaction was promoted by a bromonium cation and moderate to high yields of oxetanes 50 were obtained. The authors claim the reaction was diastereospecific for disubstituted

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 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

Selective monoformylation of naphthalene-fused propellanes for methylene-alternating copolymers

• Kenichi Kato,
• Tatsuki Hiroi,
• Seina Okada,
• Shunsuke Ohtani and
• Tomoki Ogoshi

Beilstein J. Org. Chem. 2025, 21, 1183–1191, doi:10.3762/bjoc.21.95

• blocks, we herein report electrophilic formylation of naphthalene-fused [3.3.3]- and [4.3.3]propellanes as the first selective single-point functionalization by virtue of through-space electronic communications between the naphthalene units. The propellane skeletons have well-defined 3D structures and

• a single functional group to a whole skeleton of [4.3.3] and [3.3.3], using formylation [55][56]. The reaction is electrophilic, and the substrates are effectively deactivated toward further reactions upon introduction of an electron-withdrawing formyl group because of through-space electronic

• Supporting Information File 1). Despite several trials, the reactions led to complicated mixtures owing to decomposition and debromination or predominant recovery of the starting material, respectively. Then, we turned our attention to electrophilic formylation. Vilsmeier–Haack [61] and Duff [62] reactions

Enhancing chemical synthesis planning: automated quantum mechanics-based regioselectivity prediction for C–H activation with directing groups

• Julius Seumer,
• Nicolai Ree and
• Jan H. Jensen

Beilstein J. Org. Chem. 2025, 21, 1171–1182, doi:10.3762/bjoc.21.94

• electrophilic aromatic substitution and a proton abstraction mechanism via CMD, where they calculated the relative energies of the intermediates. Using their workflow, they were able to predict correctly the regioselectivity for 18 tested substrates. The main limitation of this work is the computational cost

• groups following the CMD mechanism. This workflow employs (semi-empirical) quantum calculations in a hierarchical way to predict regioselective outcomes, delivering results within seconds to minutes. For substrates that are expected to follow the electrophilic aromatic substitution mechanism without the

• influence of DGs, we refer the reader to previous work done by Kromann et al. [15] and Ree and colleagues [16][17]. The there developed RegioSQM predicts the regioselectivity of reactions following the electrophilic aromatic substitution mechanism within seconds to minutes using a web interface or a Python

Supramolecular assembly of hypervalent iodine macrocycles and alkali metals

• Krishna Pandey,
• Lucas X. Orton,
• Grayson Venus,
• Waseem A. Hussain,
• Toby Woods,
• Lichang Wang and
• Kyle N. Plunkett

Beilstein J. Org. Chem. 2025, 21, 1095–1103, doi:10.3762/bjoc.21.87

• -deficient in nature owing to the presence of three electron-deficient iodine atoms within the macrocycle's framework. To better understand the electrophilic environment of the macrocyclic cavity, we have calculated the Mulliken charges on each atom of Phe HIM 1. To analyze the resultant charge of the

• macrocycle is electrophilic in nature. In addition, DFT results show the three outwardly projected carbonyl oxygens (formerly the carbonyl of benzoic acid) are negatively charged and can potentially bind or interact with metal cations. Figure 3 (right) shows the calculated electrostatic potential map with

• the area of the electrophilic cavity of HIM (shown in red) being smaller, which suggests lower electron density. In contrast, the red areas of the three outwardly projected carbonyl oxygens (formerly the carbonyl of benzoic acid) are larger, demonstrating the higher overall electron density of that

Recent advances in synthetic approaches for bioactive cinnamic acid derivatives

• Betty A. Kustiana,
• Galuh Widiyarti and
• Teni Ernawati

Beilstein J. Org. Chem. 2025, 21, 1031–1086, doi:10.3762/bjoc.21.85

• the electrophilic triazinedione, releasing DMAP to give ester 15 which reacts with DMAP to afford the active N-acylpyridinium species 16. In addition, N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC·HCl), a common coupling reagent, has been applied for a continuous flow

• reagent (Scheme 7) [38]. By mimicking the electrophilic sp-carbon center of common coupling reagents (e.g., DCC, EDC), Zhao and co-workers (2021) employed allenone 22 as a coupling reagent for amidation [39]. Herein, cinnamic acid was smoothly converted to its corresponding amide 10 in a one-pot two-step

• amidation in 5 min reaction time via the formation of the isolable enol ester intermediate 23 (Scheme 8A). Similarly, Feng and co-workers (2019) studied one-pot two-step esterification of cinnamic acid (7) by applying electrophilic sp carbon center of methyl propiolate (25) as the coupling reagent via in

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

• incorporated into cyclization reactions. The iminium species generated from enamides via nucleophilic addition or substitution are capable of engaging in further electrophilic additions or isomerization processes. Exploiting the multiple reactivities of enamides facilitates the development of diverse

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

• for the in situ generation of hydrogen cyanide (Scheme 1a). This method achieved high regioselectivity and enantioselectivity, highlighting the potential of allene hydrocyanation for the synthesis of complex nitrile-containing products. In another approach, the Minakata group used electrophilic

• -catalyzed regioselective hydroalumination of allenes using diisobutylaluminum hydride (DIBAL-H), we envisioned that the nucleophilic attack of allylaluminum reagents on electrophilic cyanating reagents could provide a regioselective pathway for the synthesis of alkyl nitriles bearing quaternary carbon

• in 85% and 93% yield, respectively. Unfortunately, the 1,1,3-trialkyl-substituted allene 1aa was not suitable for Cu-catalyzed hydroalumination under the established conditions, resulting in less than 2% conversion to allylaluminum reagents. In a previous study on the electrophilic cyanation of

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

• reaction proceeded with electrophilic iodination of aromatic compounds followed by a nucleophilic reaction of the formed phosphorothioate intermediate to give corresponding S-heteroaryl phosphorothioates in good to excellent yields (Scheme 29). In 2023, Liu et al. [70] reported an interesting

• reaction system. The reaction proceeded via an anodic oxidation of bromide to bromine, followed by a reaction with sulfur and dialkylphosphite to give the corresponding dialkylphsophothioate. The reaction proceeded via an electrophilic aromatic substitution in the next step to provide the final product

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

• internal rotation in 11 via TS8 and reaction with TMSCN to give adduct 13 (see Figure 3). Distances and bond lengths are given in pm. Catalyst 7 is replaced in TS 11-12 by concerted electrophilic intramolecular substitution with formal trimethylsilyl cation as electrophile. Please note the surprisingly

Synthesis of HBC fluorophores with an electrophilic handle for covalent attachment to Pepper RNA

• Raphael Bereiter and
• Ronald Micura

Beilstein J. Org. Chem. 2025, 21, 727–735, doi:10.3762/bjoc.21.56

• with an electrophilic handle for the covalent attachment of the surrogate to the RNA. The resulting irreversibly tethered dye–RNA complexes have opened up new avenues for RNA imaging in live cells. Here, we report the syntheses of such modified HBC530 ((4-((2-hydroxyethyl)(methyl)amino)benzylidene

• fluorophores that provide the parent HBC530 ((4-((2-hydroxyethyl)(methyl)amino)benzylidene)cyanophenylacetonitrile) stilbene core [7] but offer an electrophilic alkyl handle on the amino group replacing the original N-hydroxyethyl residue. Three of them have been applied in the cellular applications (Brc3HBC

• (8), MsOc3HBC (14), and MsOc3HBC-vinyl (22)) as reported previously [11]. Nine more HBC derivatives with altered handle lengths and different electrophilic groups are introduced in this study. Furthermore, we include an evaluation of the efficiency of all reactive fluorophores (previously introduced

Acyclic cucurbit[n]uril bearing alkyl sulfate ionic groups

• Christian Akakpo,
• Peter Y. Zavalij and
• Lyle Isaacs

Beilstein J. Org. Chem. 2025, 21, 717–726, doi:10.3762/bjoc.21.55

• to a sulfate group. The synthetic route to C1 starts with the double electrophilic aromatic substitution reaction of methylene-bridged glycoluril tetramer (TetBCE) with W1 in TFA/Ac2O 1:1 which adds the sidewalls and transforms the OH groups into OAc groups to give TetW1OAc in 71% yield as described

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

• -chair conformations of the oxocarbenium intermediate (Figure 9) [131][132]. Also, in the preferred pucker, the C–F bond is oriented orthogonal to the C=O group, which makes the carbonyl more electrophilic through mixing of the π*C=O orbital with the σ*C–F orbital. These combined effects enhance both the

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

• -trifluoromethylalkenes 38 with hydrosilanes and allylic chlorides 40 (Scheme 14b) [55]. In their work, a chiral α-CF3 alkylcopper intermediate 39 was formed through the regio- and enantioselective hydrocupration of electron-deficient alkenes 38 with an in situ-generated CuH species. Subsequent electrophilic trapping of