Recent advances in copper-catalyzed direct hydroamination of alkenes with (hetero)aromatic amines

• Hyejeong Lee and
• Yunmi Lee

Beilstein J. Org. Chem. 2026, 22, 925–947, doi:10.3762/bjoc.22.73

• suitable ligands such as N-heterocyclic carbenes or electron-rich phosphines, the deprotonation of an N–H heteroaromatic can generate a copper–amido intermediate [32][33][34]. These species typically exhibit enhanced nucleophilicity and can engage alkenes via the direct nucleophilic addition of a copper

• characterization of well-defined copper–amido complexes I and II, supported by electron-donating ligands such as phosphines and N-heterocyclic carbenes (NHCs) (Scheme 2) [32][33][34]. Copper–amido complex I was prepared by treating the dtbpe-ligated Cu–Cl complex (dtbpe = 1,2-bis(di-tert-butylphosphino)ethane

• bond formation. Structural and reactivity studies revealed that electron-rich ligands stabilized the copper center while facilitating the formation of copper–amido intermediates, consequently enhancing the nucleophilicity of the nitrogen atom. The catalytic activities of complexes I and II (Scheme 2

A practical CO₂-mediated synthesis of 5,6-carboxylated silicon-rhodamines for targeted probe development

• Dongjie Hou,
• Shaowei Wu,
• Ning Xu,
• Pengjun Bao,
• Wenhao Jia,
• Qinglong Qiao and
• Zhaochao Xu

Beilstein J. Org. Chem. 2026, 22, 915–924, doi:10.3762/bjoc.22.72

• maturity of photophysical optimization, the broader expansion of SiR chemistry is increasingly constrained by the limited accessibility of 5,6-carboxylated SiR derivatives. The carboxy groups provide a general and efficient handle for amide coupling with targeting ligands and are therefore central to the

• derivatives can be directly used in subsequent amidation reactions with targeting ligands without column chromatography, facilitating the rapid construction of high-performance targeted fluorescent probes. Overall, this strategy provides a straightforward, efficient, and practical synthetic route for the

• functionalization with HaloTag ligands through a one-pot sequence (Figure 2b). After treatment of compounds 1a–c with n-BuLi and CO2, the reaction mixtures were extracted with ethyl acetate and concentrated, and the resulting crude carboxylated intermediates were directly subjected to amide coupling with the

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

• intriguing moiety in biologically active compounds (e.g., natural products used for medicines, quinine, and quinidine [5][6][7]) and synthesized pharmaceutical agents (e.g., quinolone antibiotics [8]). Moreover, quinoline-2-carboxamide derivatives are used as ligands in organic synthesis owing to their high

• metal affinity [9][10]. It is therefore expected that annulation of the amide moiety in quinoline-2-carboxamides would extend their functionality as biologically active structures, ligands, and extractants. Transition-metal-catalyzed coupling reactions are crucial for constructing carbon–carbon and

• ]. Additionally, intramolecular C–H arylation reactions with N-heteroaromatics can be used to synthesize various functional molecules that serve as ligands for metal extraction [36][37][38][39][40][41]. Our group developed a cyclization reaction for the intramolecular C–H arylation with N-heterocycles, such as

Site-specific labelling of native peptides and proteins: chemical and enzymatic strategies

• Antonio Angelastro,
• Jonathan Bargh,
• Subhajit Guria,
• Victor Laserna and
• Louis Luk

Beilstein J. Org. Chem. 2026, 22, 857–881, doi:10.3762/bjoc.22.67

• these options are unsuitable, other solvent-exposed nucleophilic residues (e.g., methionine, histidine, tryptophan, tyrosine or arginine) can be targeted, although such reagents are often prepared in-house and may lack positional control. When high-affinity ligands or binders are available, affinity

The trans-influence in gold chemistry from a catalytic perspective

• Manfred Bochmann

Beilstein J. Org. Chem. 2026, 22, 838–856, doi:10.3762/bjoc.22.66

• recent mechanistic insights. Keywords: catalysis; gold; ligands; reaction mechanism; trans-influence; Introduction Gold catalysts have emerged as catalysts of choice in a multitude of organic transformations, not least due to their high functional group tolerance. Their applications have been widely

• documented in monographs and special themed journal issues, see for example [1][2][3][4][5][6][7][8][9][10]. Of special interest here are gold complexes supported by bidentate and tridentate ligands; their chemistry has been the subject of a number of reviews, covering different aspects of structure, bonding

• -mediated reaction mechanisms. Following a brief discussion of general considerations, this Perspective examines how ligand structure and the resulting trans-influence determine reactivity and stability of gold(III) complexes supported by tridentate (pincer) ligands and in bidentate chelates, including

Unsymmetrical sulfoxides with sterically hindered catechol fragment: synthesis, structure, electrochemical properties, and antiradical activity

• Daria A. Burmistrova,
• Vasiliy A. Fokin,
• Oleg P. Demidov,
• Mikhail A. Kiskin,
• Maxim V. Arsenyev,
• Andrey I. Poddel’sky,
• Nadezhda T. Berberova and
• Ivan V. Smolyaninov

Beilstein J. Org. Chem. 2026, 22, 828–837, doi:10.3762/bjoc.22.65

• antioxidants, stimuli-responsive materials, and functional ligands for metal complexes with tailored electronic properties. Molecular structures of 1a (a), 4a (b), 5a (c), 6a (d), 7a (e) (solvent molecules and fragment disordering are omitted; for 4a and 5a, only one independent molecule is shown). CV curves

Knoevenagel condensation of 4,5- and 1,8-diazafluorenes

• Darya S. Cheshkina,
• Christina S. Becker,
• Alina A. Sonina and
• Maxim S. Kazantsev

Beilstein J. Org. Chem. 2026, 22, 803–812, doi:10.3762/bjoc.22.62

• Darya S. Cheshkina Christina S. Becker Alina A. Sonina Maxim S. Kazantsev N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, Lavrentieva 9, 630090 Novosibirsk, Russia 10.3762/bjoc.22.62 Abstract Diazafluorenylidenes are potential antitumor agents, ligands, and functional materials

• with ketones resulted in unique di(pyridin-2-yl)methylene)-9H-diazafluorenes being electron-deficient ligands and functional materials. Keywords: acidic conditions; diazafluorene; diazafluorenylidene; Knoevenagel condensation; protonation; Introduction Diazafluorenylidene derivatives were reported to

• be applied as antitumor agents [1][2][3], emitters and sensors [4][5]. They have also been extensively used as ligands yielding a wide library of transition-metal complexes [6][7][8], catalysts [9][10], light-driven molecular motors [11][12], nonlinear optical chromophores [13], and electrochromic

Design, synthesis, and biological evaluation of FXR/ASK1 dual-target modulators

• Xi Zhang,
• Jingyan Wang,
• Ziqiang Zhao,
• Caiyi Wang,
• Zenghui Ye,
• Wei-Yuan Ma,
• Jian-Xing Xu and
• Fengzhi Zhang

Beilstein J. Org. Chem. 2026, 22, 771–781, doi:10.3762/bjoc.22.59

• study, we present the rational design and characterization of a balanced dual modulator targeting the nuclear receptors FXR and ASK1 [32], with the objective of advancing this experimental therapeutic concept (Scheme 3) [33][34]. The conception of this class of dual ligands was achieved by the merging

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

• chiral metal complexes of Ag(I), Cu(I/II), Zn(II), Ni(II) with ligands of the Segphos, Fesulfos, or Biphamphos type [12][13][14][15]. Such catalytic systems control the enantioselectivity of cycloaddition and allow the preparation of enantioenriched pyrrolidines containing several stereocenters in high

• authors proposed a model for the intermediate complex in 1,3-dipolar cycloaddition reactions. This intermediate consists of an azomethine ylide coordinated to a Zn(II)-t-Bu-BOX catalyst and is an 18-electron complex with a tetrahedral arrangement of ligands around the zinc center. Excellent results for

• diastereoselectivity in the catalytic (3 + 2) cycloaddition between iminoethers and electrophilic alkenes occurring using chiral metal complexes based on copper(I) and silver(I) salts and ligands (S)-DM-Segphos (L12) or (S)-DTBM-Segphos (L11) (Scheme 12). The reactions involved various dipolarophiles such as acrylates

Using generative AI to transform peptide hits into small molecule leads

• Joshua Mills and
• Yu Heng Lau

Beilstein J. Org. Chem. 2026, 22, 672–679, doi:10.3762/bjoc.22.51

• application of ML for small molecule design based on peptide datasets was reported in 2023 by Hou and co-workers, where models were trained to classify ligands as ghrelin receptor binders [21]. The complete dataset for training and evaluation consisted of 548 peptides/peptidomimetics and 2193 small molecules

• that leverages peptide-binder structural data to generate small molecules within the protein pocket. It is trained on a range of target-bound complexes, including small molecule ligands as well as peptides and protein binders [38]. Similar to DiffLinker, small molecule generation is initiated from

Advantages of PROTACs in achieving selective degradation of homologous protein families

• Luxi Yang,
• Xinfei Mao,
• Jingyi Zhang,
• Jing Shu,
• Wenhai Huang,
• Xiaowu Dong,
• Yinqiao Chen and
• Mingfei Wu

Beilstein J. Org. Chem. 2026, 22, 628–661, doi:10.3762/bjoc.22.49

• , PROTACs, one of the most extensively studied and promising TPD approaches, are reshaping the paradigm of small-molecule drug development [11]. The PROTAC technology was initially conceptualized by Crews et al. in 2001 [11]. As a heterobifunctional molecule, a PROTAC comprises two distinct ligands: one

• Influence of linkers on the selectivity of PROTACs in highly homologous protein families As previously established [37], a PROTAC molecule comprises three essential components: a POI ligand, a linker, and an E3 ligand. In drug design, POI ligands are typically derived from FDA-approved small-molecule

• inhibitors, candidates in clinical trials, or their structural analogs. Similarly, E3 ligands are engineered to target specific E3 ubiquitin ligases. For instance, pomalidomide and lenalidomide are widely employed to recruit the CRBN ligase [38]. Given the established nature of these ligands, initial

Hydrogen production from formic acid catalyzed by NHC–Cu complexes

• Orlando Santoro and
• Catherine S. J. Cazin

Beilstein J. Org. Chem. 2026, 22, 620–627, doi:10.3762/bjoc.22.48

• phenanthroline ligands (TOF 4 h−1) [48] as well as Cu(0), Cu(I), and Cu(II) precursors/NEt3 (TOFs < 1 h−1) [44]. In contrast, [Cu(NCMe)4][PF6]/phosphine ligands/(t-BuNC–NEt3) systems represent the most active Cu-based catalysts reported to date for this transformation, exhibiting TOFs spanning from 10 to 240 h−1

Towards the targeted protein degradation of CK2: design and synthesis of CAM4066-based PROTACs

• Sophie Day-Riley,
• Sona Krajcovicova,
• Aryaman Raj Sokhal,
• Jan L. Venne,
• Paul Brear,
• Marko Hyvönen,
• Benjamin C. Whitehurst,
• Jason S. Carroll and
• David R. Spring

Beilstein J. Org. Chem. 2026, 22, 611–619, doi:10.3762/bjoc.22.47

• conjugating a CAM4066-derived warhead to CRBN or VHL ligands, four VHL-recruiting PROTACs, were prepared using PEG and alkyl linkers, alongside two CRBN-recruiting analogues featuring constrained linkers. A ligand–linker analogue in which a linker is projected from the solvent-exposed region of CK2α retained

• conjugated CAM4066-derived ligands to both CRBN or VHL E3-ligase recruiters. We created VHL-recruiting PROTACs for CK2 using PEG and alkyl linkers, while the CRBN-recruiting analogues featured more constrained linkers. A ligand–linker analogue bearing a linker projected from the solvent-exposed region of the

• map revealed that it remained solvent-exposed and sterically accessible, validating the design for subsequent attachment of E3-ligase ligands. With the exit vector validated, the synthesis of full PROTACs was pursued. The VH032-derived VHL ligand 21 (for full synthesis see Supporting Information File

Design and synthesis of an erdafitinib-based selective FGFR2 degrader

• Yumeng Jin,
• Shidong Wang,
• Sihan Pan,
• Shuqi Huang,
• Weichen Zhou,
• Xiaohao Huang,
• Lei Zheng and
• Lingfeng Chen

Beilstein J. Org. Chem. 2026, 22, 583–591, doi:10.3762/bjoc.22.44

• binding to ligands, which trigger intracellular signaling cascades to activate downstream substrates and pathways [4]. This process involves PLC γ-mediated PKC activation and pFRS2-induced activation of the PI3K/AKT and MAPK/ERK pathways, thereby regulating cell proliferation, differentiation, migration

• effectively degrade FGFR2 via the proteasomal pathway, while the VHL E3 ligase-based degrader DGY-09-192 is capable of degrading both FGFR1 and FGFR2 simultaneously [40]. These findings suggest that different E3 ligase ligands may influence the selectivity and efficiency of degradation [41]. Nevertheless, due

Kinetic resolution of racemic planar-chiral vinylcymantrenes by molybdenum-catalyzed asymmetric metathesis dimerization

• Haruna Imazu,
• Hitoshi Izu,
• Yasuhiro Ohki and
• Masamichi Ogasawara

Beilstein J. Org. Chem. 2026, 22, 568–574, doi:10.3762/bjoc.22.42

• in Figure 2) likely inhibits the effective interaction of the substrate with the chiral catalyst, resulting in highly enantioselective kinetic resolution. Cymantrene is far less electron-poor than ferrocene due to the presence of the three carbonyl ligands, which are strong π-acids, on the manganese

Molecular tweezer–peptide conjugates disrupt the protein–protein interaction between survivin and histone H3 essential in mitosis

• Catherine Gsell,
• Philipp Rebmann,
• Karina Opara,
• Christine Beuck,
• Peter Bayer,
• David Bier,
• Ingrid R. Vetter and
• Thomas Schrader

Beilstein J. Org. Chem. 2026, 22, 557–567, doi:10.3762/bjoc.22.41

• crystal (Figure 4 and Supporting Information File 1, Figure S12). Lys-121, on the other hand, is buried in a crystal contact. Thus, the crystal packing forces together with putatively competing ligands (see below) can apparently compete successfully with the tweezer that is most likely attached to Lys-121

Experimental and DFT studies on the regioselective methanolysis of 5-azido-9-oxabicyclo[6.1.0]nonan-4-yl 4-nitrobenzoate isomers

• İlknur Polat,
• Selçuk Eşsiz and
• Emine Salamci

Beilstein J. Org. Chem. 2026, 22, 547–556, doi:10.3762/bjoc.22.40

• , pharmaceutical compounds, and chiral ligands. The Lewis acid-catalyzed ring-opening reaction of cyclohexene oxide by MeZH (Z = O, S, and NH) is well known [20]. However, studies on large-sized bicyclic epoxides remain relatively limited in the published literature. In our previous study, we performed the ring

Synthesis and uranyl(VI) extraction performance of a calix[4]pyrrole–tetrahydroxamic acid receptor

• Sara Karnib,
• Rana Baydoun,
• Wissam Zaidan,
• Nancy AlHaddad,
• Omar El Samad,
• Bilal Nsouli,
• Francine Cazier-Dennin and
• Pierre-Edouard Danjou

Beilstein J. Org. Chem. 2026, 22, 486–494, doi:10.3762/bjoc.22.36

• ligands can display significantly enhanced binding toward uranyl relative to their linear hydroxamic acid counterparts, emphasizing the beneficial role of structural organization in uranyl chelation [35]. This beneficial role of pre-organization of chelating groups within one molecule was also highlighted

• pH 2 and pH 3, the extraction efficiencies remain overall comparable within experimental uncertainty, suggesting that uranyl uptake is already near maximal in this acidic region. This behavior is consistent with previous studies in which ligands displayed high uranyl uptake within an optimal pH

• window. For instance, calix[4]arene-based 8-hydroxyquinoline ligands showed nearly quantitative extraction of uranyl between pH 4 and 9, with efficiency decreasing under more acidic conditions [67]. Likewise, phosphoramide-functionalized magnetic nanoparticles showed high uranyl adsorption (80–95

Synthesis of a HDAC inhibitor–nanogold probe for cryo-EM visualization in class I HDAC co-repressor complexes

• Wiktoria A. Pytel,
• John W. R. Schwabe and
• James T. Hodgkinson

Beilstein J. Org. Chem. 2026, 22, 480–485, doi:10.3762/bjoc.22.35

• , specifically Monoamino-Nanogold® 1.4 nm purchased from Nanoprobes) for our probe design. Au–NH2 consists of a gold cluster of eleven gold atoms coordinated by trisarylphosphine ligands with a diameter of 1.4 nm. One of the trisarylphosphine ligands contains the 3-aminopropylamido group, allowing for

Recent advances in the stereoselective synthesis of distal biaxially chiral molecules

• Fanxing Zhou,
• Chen Zhang,
• Lingyu Sun,
• Yiyun Fang,
• Siming Zheng,
• Lina Hu,
• Mengyang Shen,
• Zhen Zhao,
• Wei Xu,
• Yunqiang Sun and
• Zi-Qiang Rong

Beilstein J. Org. Chem. 2026, 22, 461–479, doi:10.3762/bjoc.22.34

• distal axial chiralities are widely applied in chiral ligands, natural products, and anticancer agents, with their unique spatial configurations endowing them with distinctive functions and values. Although significant progress has been made in the asymmetric synthesis of distal biaxial chirality

• chiral scaffolds, which arise from hindered rotation between two planes connected by a single bond, have attracted increasing attention due to their widespread applications in chiral ligands, organocatalysts [1], and functional materials [2], making them highly valuable molecular frameworks in organic

• ligands (Scheme 3) [44]. The resulting catalysts 18 demonstrated remarkable efficiency in the asymmetric transfer hydrogenation of quinoline derivatives. Along similar lines, Zhang and co-workers introduced an additional axial chirality element into a ligand framework, affording a pair of diastereomeric

Synthesis and anti-cancer activity of naphthalimide–organylselanyl conjugates

• Rajkumar Ravi and
• Selvakumar Karuthapandi

Beilstein J. Org. Chem. 2026, 22, 416–435, doi:10.3762/bjoc.22.29

• conformation (4HJO). The docking results revealed that both ligands fit well within the binding pocket of the EGFR tyrosine kinase domain. The binding interactions were further validated by comparison with the crystal structures of the active (1M17) and inactive (4HJO) forms of EGFR complexed with the co

• ), hydrogen bonding (Met769), carbon–hydrogen bonding (Thr766), π–anion (Asp831), π–σ (Leu694), amide–π (Met769), alkyl (His781), and π–alkyl (Val702, Ala719, Leu768, Leu820). These results confirm that both ligands are well accommodated within the binding pocket of EGFR tyrosine kinase, with compound 7

• site interactions to those observed for erlotinib. Both erlotinib and the synthesised ligands formed a hydrogen bond interaction with Met769. The synthesised ligands have a greater ability to form an interaction with the active (1M17) tyrosine kinase domain of EGFR. Comparative binding interaction of

Arene activation via π-bond localization: concepts and opportunities

• Paul Meiners,
• Julian J. Melder and
• Tobias Morack

Beilstein J. Org. Chem. 2026, 22, 257–273, doi:10.3762/bjoc.22.19

• of the archetypal pentaammineosmium(II) system prior to discussing synthetic utility (Figure 6). The five ammine ligands, strong σ-donors with negligible π-interaction, combined with the d6 configuration render the Os(II) center highly electron-rich and an exceptional π-base [43]. This electronic

• configuration promotes strong binding to π-acidic ligands, effectively compensating for the loss of aromaticity upon η2-coordination to arenes, while disfavoring oxidative addition due to geometric constraints of the octahedral complex. The resulting η2-arene complexes, encompassing both arenes and heteroarenes

• (Figure 6C), so suitable aromatic ligands are limited to those lacking strongly π-acidic functional groups, e.g., alkenes, alkynes, aldehydes, certain ketones, and nitriles. Lewis-basic heteroarenes, such as pyridines or imidazoles, tend to coordinate via nitrogen instead, disfavoring η2-binding (Figure

Screwing the helical chirality through terminal peri-functionalization

• Devesh Chandra,
• Sachin and
• Upendra Sharma

Beilstein J. Org. Chem. 2026, 22, 205–212, doi:10.3762/bjoc.22.14

• another important type of chirality, where the chirality is controlled by restricted rotation among an axis. These types of molecules play an important role as chiral ligands in organic synthesis, i.e., BINOL, BINAP, etc. [9][10][11]. Another form of chirality, where chirality depends on a constrained

• asymmetric synthesis, where they serve as chiral ligands and organocatalysts, delivering high enantioselectivities [17][18]. Their tunable HOMO–LUMO gaps and controlled π–π interactions, is key to the use of helicenes in molecular electronics and organic semiconductors as well. Helicenes function as active

Improved synthesis and physicochemical characterization of the selective serotonin 2A receptor agonist 25CN-NBOH

• Adrian G. Rossebø,
• Hannah G. Kolberg,
• Anders E. Tønder,
• Louise Kjaerulff,
• Poul Erik Hansen,
• Karla A. Frydenvang,
• Jesper Østergaard and
• Jesper L. Kristensen

Beilstein J. Org. Chem. 2026, 22, 175–184, doi:10.3762/bjoc.22.11

• agonists to study the effects of solely activating this key receptor [4]. 25CN-NBOH (1) was reported in 2014 as part of a series of ligands in the search for selective 5-HT2AR agonists [5]. Subsequently, it has been used and characterized extensively as a tool for investigations into the effects of

Design and synthesis of an axially chiral platinum(II) complex and its CPL properties in PMMA matrix

• Daiki Tauchi,
• Sota Ogura,
• Misa Sakura,
• Kazunori Tsubaki and
• Masashi Hasegawa

Beilstein J. Org. Chem. 2026, 22, 143–150, doi:10.3762/bjoc.22.7

• , pincer-type platinum(II) complexes have attracted particular attention, owing to the structural robustness imparted by tridentate chelating ligands and their excellent luminescent properties [12][13][14][15][16][17]. These complexes have been widely investigated, not only for practical application but

• arrangement of several molecules in the aggregated state. To expand the scope of chirality in metal complex chemistry with pincer ligands and to facilitate the design of next-generation CPL-active materials, alternative chiral motifs beyond point chirality are highly desirable. Herein, we report the design