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

• an electrophilic handle for the covalent attachment of the ligand to the RNA. The simplicity of the underlying design of irreversibly bound ligand–RNA complexes has provided a new impetus in the fields of covalent RNA labeling and RNA drugging. Here, we present short and robust synthetic routes for

• mRNA domain, namely the preQ1 class-I riboswitch (preQ1-I) from Thermoanaerobacter tengcongensis. By rigorously analyzing the high-resolution structures available for this ligand–RNA complex, the approach exploits the natural, sequence-inherent reactivity hotspots of RNA and thus avoids the use of

• 3b in almost quantitative yield. The bis(3-bromopropyl)-modified ligand 3c was generated by heating preQ1 together with bis(3-hydroxypropyl)amine. It is noteworthy that the amine exchange reaction is thought to proceed via a purine methide intermediate [11]. Subsequent treatment of the diol with

Beyond symmetric self-assembly and effective molarity: unlocking functional enzyme mimics with robust organic cages

• Keith G. Andrews

Beilstein J. Org. Chem. 2025, 21, 421–443, doi:10.3762/bjoc.21.30

• formation possible in metal–ligand bonding provides chemists with a shortcut to access 3D scaffolds. When well-designed linkers and metals are combined, discrete cages emerge as the thermodynamic product (Figure 5A) [22][142][143][144]. Typically, rigid linkers are required to enforce geometry, although a

• compartmentalization of contrasting reactivities is possible to avoid such incompatibilities [189][199][200][201]. Likewise, the lability of metal–ligand dative bonds can make post-assembly modifications of MOCs challenging [202][203] – for instance it is difficult to lock the dative bonds in place, and reactions that

• chemistry [200]. “Switchable” metal-organic cages [212] use a stimulus like light to change ligand geometries. This often triggers disassembly since new geometries can lead to new thermodynamic minima, though where geometric changes are tolerated within the original structure the stimuli can trigger guest

Red light excitation: illuminating photocatalysis in a new spectrum

• Lucas Fortier,
• Corentin Lefebvre and
• Norbert Hoffmann

Beilstein J. Org. Chem. 2025, 21, 296–326, doi:10.3762/bjoc.21.22

• and a given substrate or a sacrificial species. In the case of the metal-based complexes, the absorption band associated to the metal-to-ligand charge transfer (MLCT) is generally addressed even though other types of excitations like ligand-to-metal charge transfer, ligand- and metal-based excitation

• have been proven to be efficient in photoredox catalysis [9][10][11][12]. Actually, MLCT enables a charge separation for which the ligand-based electron can trigger a chemical reduction while the metal-centered hole, a chemical oxidation. This type of excitation is particularly enhanced in heavy metals

• , where the low-lying excited state often corresponds to the metal-to-ligand charge transfer (MLCT) transition. As the atomic number increases, relativistic effects become more pronounced, leading to the contraction of s and p orbitals while the d and f orbitals expand and become more diffuse. While these

Visible-light-promoted radical cyclisation of unactivated alkenes in benzimidazoles: synthesis of difluoromethyl- and aryldifluoromethyl-substituted polycyclic imidazoles

• Yujun Pang,
• Jinglan Yan,
• Nawaf Al-Maharik,
• Qian Zhang,
• Zeguo Fang and
• Dong Li

Beilstein J. Org. Chem. 2025, 21, 234–241, doi:10.3762/bjoc.21.15

• mixture, which significantly impeded the progress of the desired reaction. Therefore, on the basis of the above experimental results and previous reports [21][27][28][29][30], we proposed a possible reaction mechanism (Scheme 3b), taking CF2HCOOH as the illustrative example. Initially, a double ligand

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

• , the Chang group elegantly unveiled a protocol for an enantioselective C–N bond formation, introducing δ-lactams from dioxazolones using a copper(I) catalyst and a chiral BOX ligand [74]. As shown in Scheme 2, dioxazolones containing aryl and heteroaryl groups were converted into the corresponding

• conducted using a catalytic amount of copper acetate and a phenanthroline ligand, with a stoichiometric amount of silane serving as the reductant. Both aryl- and alkyl-substituted dioxazolones proved to be compatible under the standard reaction conditions, yielding the desired primary amides 28a–f. Notably

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

• decreasing the oxidation potential. A range of functional groups, such as halides, ethers, and heterocycles, were tolerated well, yielding the corresponding enantioenriched products 14 with high enantioselectivity in the presence of chiral bisoxazoline ligand L2. A possible mechanism is depicted in Figure 5

• quinine as a chiral ligand under standard conditions, the chiral product was obtained with a high yield and 79% ee. Enantioselective C(sp3)–H functionalization is an attractive strategy for synthesizing chiral molecules. Significant progress has been achieved in transition-metal-catalyzed asymmetric C–H

• . Subsequent intramolecular amine transfer to the radical cation intermediate 53, followed by ligand exchange, yields amination product 49 and Cu(I) species 55. Cu(II) catalyst 50 is regenerated by anodic oxidation, thereby completing the catalytic cycle. In 2019, Nicholls et al. reported a Cu-catalyzed

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

• catalyst, PCy3 (20 mol %) as a ligand, and K2CO3 (2.0 equiv) as a base, the desired arylated naphthofuran 3bb was obtained in 75% yield (Table 1, entry 1). Reducing the reaction temperature improved the yield of 3bb, reaching a quantitative yield when the reaction was performed at room temperature (Table 1

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

• known processes, a particular Mannich-type reaction was realized in water in the presence of a dendritic 2,2’-bipyridine ligand 2 and Cu(OTf)2 (Scheme 2) [16]. The hydrophobic ligand surrounding the metal revealed to be essential for the organic synthesis in water, thus increasing the reaction yields

• the coupling with copper triflate as catalyst, without ligand, co-catalyst or other additives. The reaction involved the formation of the imine XVII followed by alkynylation to propargylamine XVIII, cyclization, and oxidation to quinoline 23 (Scheme 17) [34]. Three component oxidative annulation to

• -methylthiazole-2-carboxaldehyde as chelating agent, in the presence of copper triflate and the chiral diamine ligand 28. The stereoselectivity was directed by the formation of a proposed catalyst complex 29 involving two molecules of Schiff base (Scheme 22) [39]. The three-component annulation of aldehydes

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

• transformed through a series of reactions to a diphenylphosphine group and used as a ligand for Pd-catalyzed reactions. De novo ring formation was utilized in the synthesis of N–N axially chiral N-pyrrolylindoles 98 and N-pyrrolylpyrroles 100 with the help of CPA C27 (Scheme 31) [55]. Starting from either

• a CPA to be used as an organocatalyst or to a phosphoramidite to be used as a chiral ligand. Testing these new structures on known stereoselective transformations, the authors achieved high yields and enantioselectivities (up to 98% yield and 97% ee). Wang et al. performed asymmetric (4 + 3

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

Synthesis, structure and π-expansion of tris(4,5-dehydro-2,3:6,7-dibenzotropone)

• Yongming Xiong,
• Xue Lin Ma,
• Shilong Su and
• Qian Miao

Beilstein J. Org. Chem. 2025, 21, 1–7, doi:10.3762/bjoc.21.1

• yield of 90%. Then, the Ni-mediated Yamamoto coupling reaction of 6 enabled cyclotrimerization to give trione 1 in a yield of 30%. It is worth mentioning that using 1,10-phenanthroline as the ligand in the Yamamoto coupling [25][26] led to a higher yield of compound 1 than using 2,2’-bipyridine. With

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

• ) ligand 4 were reported by Cowley and co-workers in 2010 [14]. In addition to heterocyclic fluoranthene analogues, highly oxygenated benzo[j]fluoranthenes are commonly encountered fungal natural products with important biological activities [15]. Bulgarein (5) is an example of such a benzo[j]fluoranthene

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

• % yield. The yield is improved to 94% when the reaction is performed with PPh3 as a ligand of palladium. The reaction is examined with amides derived from unsubstituted picoline, 6-methylpicoline, and 2,6-pyridinedicarboxylic acid in a similar manner to afford the cyclized products in 70%, 77%, and 87

• ; phosphine ligand; pyridine amides; Introduction Transition-metal-catalyzed synthetic reactions have recently attracted much attention in synthetic organic chemistry [1][2]. C–H Arylation reactions catalyzed by a transition metal are of particular interest because these reactions involve rather superior

• resulted in a decreased yield (27%) (Table 1, entries 4 and 5). It was found that increasing the amount of potassium carbonate to a three-fold excess improved the yield of 2a to 59% in the reaction at 110 °C shown in entry 6 of Table 1. Next, the effect of the ligand of the palladium catalyst was examined

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

• donepezil, employing a widely accepted tauopathy model in SH-SY5Y cells. Notably, compound 7a was identified as the most promising multitarget-directed ligand in the study, exhibiting superior neuroprotection compared to both MK-886 and the commercial drug donepezil in a cell viability MTT assay. These

• proposed as promising neuroprotective targets in several chronic progressive disorders such as AD and PD [51]. Recently, in 2023, Figuerola-Asencio et al. [52] synthesized a series of novel compounds derived from ML192, an antagonist ligand for GRP55. This receptor responds to certain cannabinoids

• , among others. Ugi reaction: The D2 dopamine receptor (DRD2) is the target of different drugs, including antipsychotics, antiparkinsonian agents, and addiction-related disorders. Aripiprazole and cariprazine are prototypes of newer antipsychotic drugs with a bitopic ligand structure, which includes both

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

• proposed by the authors (Scheme 3). Activation of the HVI reagent by H-bonding leads to ligand exchange to give an aminofluoro iodonium intermediate A. Cyclisation occurs via nitrogen attack on the alkene to then give aziridinium intermediate B. Subsequent nucleophilic attack by fluoride on the more

• iodoarene difluoride 10 being generated from iodosylarene 9 (ArI=O) and HF, with iodosylarene itself generated by aryl iodide and m-CPBA. Ligand exchange of iodoarene difluoride with nitrogen and reaction with the alkene forms aziridinium intermediate A which, after nucleophilic attack by fluoride, forms

• (Scheme 10). The selectivity of the reaction was also found to be influenced by the presence of electrolytes like TBABF4, and the ligand attached to I(III). Carboxyfluorination was observed, in which a ligand from the iodane, e.g., OAc, OPiv or o-I-OBz, adds and was found to compete with fluoroamination

Advances in the use of metal-free tetrapyrrolic macrocycles as catalysts

• Mandeep K. Chahal

Beilstein J. Org. Chem. 2024, 20, 3085–3112, doi:10.3762/bjoc.20.257

• hydrogen–hydrogen (H–H) bond formation. This mechanism differs from metalloporphyrins, where both the metal and the ligand are redox-active [120]. Considering the potential of metal-free porphyrins as promising electrocatalysts, researchers have also investigated similar macrocycles, such as corroles, for

Cyclodextrin-based rotaxanes for polymer materials: challenge on simultaneous realization of inexpensive production and defined structures

• Yosuke Akae

Beilstein J. Org. Chem. 2024, 20, 3026–3049, doi:10.3762/bjoc.20.252

• first example of the synthesis of CD-based rotaxanes was reported by Ogino in 1981 (Scheme 1A) [36]. The hydrophobic interaction between the α-CD cavity and the alkyl chain of α,ω-diaminoalkane yielded the inclusion complex structure, and the ligand exchange between the amino groups on the axle ends and

Advances in radical peroxidation with hydroperoxides

• Oleg V. Bityukov,
• Pavel Yu. Serdyuchenko,
• Andrey S. Kirillov,
• Gennady I. Nikishin,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2024, 20, 2959–3006, doi:10.3762/bjoc.20.249

• presented in Scheme 12. The reaction probably begins with the oxidation of M(II) by TBHP into M(III) to form the tert-butoxy radical A, which abstracts a hydrogen atom from the substrate, generating the C-centered radical B. Peroxocomplex C, which can be formed from M(III)OH and TBHP as a result of ligand

• generate the nucleophilic carbon radical B. The intramolecular 1,5-HAT of B provided the alkyl radical C, which then cross-coupled with the in situ-generated high-valent Mnn+1OO-t-Bu species to form the 1,6-difunctionalized product 42 via peroxy-ligand transfer. The remote trifluoromethylthiolation

• -scale syntheses demonstrated that the protocol is practical and useful for preparation of the γ-carbonyl peroxides. The authors propose the following reaction mechanism: initially Co(II) is oxidized by TBHP to form Co(III)OH and the tert-butoxy radical. In result of ligand exchange with TBHP or acetic

Structure and thermal stability of phosphorus-iodonium ylids

• Andrew Greener,
• Stephen P. Argent,
• Coby J. Clarke and
• Miriam L. O’Duill

Beilstein J. Org. Chem. 2024, 20, 2931–2939, doi:10.3762/bjoc.20.245

• ligand occupies the position trans to the ylid substituent, with the aryl substituent in the equatorial position. Substituents on hypervalent iodine compounds can interconvert via Barry pseudorotation [31] and, interestingly, the crystal structure for compound 1i contains two isomers in its unit cell

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

• five to seven-membered cyclic compounds [47]. Arylation reactions using diaryliodonium salts can occur through four distinct mechanisms. First, the arylation can occur under metal-free conditions, involving the formation of a three-membered ring transition state through ligand coupling, leading to the

• formation of the Nu–Ar product and aryl iodide [21]. Second, the arylation can take place in the presence of a metal catalyst via oxidative addition, followed by reduction elimination [48][49]. Thirdly, it proceeds through a ligand-coupled arylation which involves a five-membered transition state to yield

• upon binding of the enolate molecule to iodine either through a carbon–iodine or an oxygen–iodine bond. Both intermediates, I and II, are in rapid equilibrium with each other and further undergo two different types of reactions: [1,2]-ligand coupling and [2,3]-rearrangement (Scheme 2). Either of these

N-Glycosides of indigo, indirubin, and isoindigo: blue, red, and yellow sugars and their cancerostatic activity

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 2840–2869, doi:10.3762/bjoc.20.240

• -glycosylated indirubins act as a ligand for the aryl hydrocarbon receptor (AhR) and also directly inhibit several cyclin-dependent kinases (CDK). A problem is generally the low water solubility of these compounds. The commercially available indirubin-3’-monoxime (34) shows a better solubility, due to the

• collaboration with Jürgen Eberle and his team it was shown that selenoindirubin-N-glycosides β-38a–h showed antiproliferative activity against lung cancer cell lines H157 [38]. The antiproliferative activity against melanoma cells was accompanied by induced apoptosis in combination with the death ligand TRAIL

• (TNF-related apoptosis-inducing ligand). The death ligand TRAIL is a promising strategy for cancer treatment. In contrast to non-glycosylated thioindirubin 35, a significant activity was observed also for non-glycosylated selenoindirubin 40h. This might be due to the fact that selenoindirubin-N

Investigation of a bimetallic terbium(III)/copper(II) chemosensor for the detection of aqueous hydrogen sulfide

• Parvathy Mini,
• Michael R. Grace,
• Genevieve H. Dennison and
• Kellie L. Tuck

Beilstein J. Org. Chem. 2024, 20, 2818–2826, doi:10.3762/bjoc.20.237

• /bjoc.20.237 Abstract The chemosensor properties of a bimetallic terbium(III)/copper(II) complex functionalized with a 4-(2-pyridyl)-1,2,3-triazole ligand for the detection of Cu2+ ions and, aqueous and gaseous hydrogen sulfide was investigated. The 4-(2-pyridyl)-1,2,3-triazole ligand functions both as

• aqueous hydrogen sulfide and 100 ppb for gaseous hydrogen sulfide [16]. However, due to the limited aqueous solubility and ligand dissociation of this chemosensor, and to the weakly luminescent bis species at usable concentrations, we extended this work to the lanthanide–macrocycle binary complexes [Ln

• in an analogous fashion to the Eu.1 complex, via a three-step synthesis as reported previously [16] and depicted in Scheme 1. The corresponding terbium(III) species was synthesized by the combination of three equivalents of the ligand L with terbium(III) trifluoromethanesulfonate under basic

Synthesis and antimycotic activity of new derivatives of imidazo[1,2-a]pyrimidines

• Dmitriy Yu. Vandyshev,
• Daria A. Mangusheva,
• Khidmet S. Shikhaliev,
• Kirill A. Scherbakov,
• Oleg N. Burov,
• Alexander D. Zagrebaev,
• Tatiana N. Khmelevskaya,
• Alexey S. Trenin and
• Fedor I. Zubkov

Beilstein J. Org. Chem. 2024, 20, 2806–2817, doi:10.3762/bjoc.20.236

• fingerprints (IFP) between the docking ligands and the protein shows that, similar to the reference ligand voriconazole, the compounds interact with the protein through hydrophobic interactions with hydrophobic residues of the protein and the formation of coordination bonds with the haem iron (Table 3). At the

• -aminoimidazole (1). Results of MEP calculations for the reaction of N-phenylithaconimide (3a) with 2-aminoimidazole (1). Screening of reaction conditions for the preparation of 7-oxo-N-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-5-carboxamide (4a). Yields of the products 4 and 5. Characterization of ligand

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

• the Suzuki coupling began with investigating first the Suzuki reaction compatibility of boronic acid 14 with porphyrin 13. Porphyrin 13 and phenylboronic acid (14) were subjected to coupling at 85 °C for 48 hours using Pd2dba3/SPhos as a catalyst/ligand giving porphyrin 26 in a 32% yield, based on a

• , even with Ni(II) metalation. There are many other methods available to achieve different desired atropisomeric ratios. These include thermal enrichment [67][68], photoracemization [69][70], axial-ligand coordination [71], precise separation techniques [50] or a combination of the procedures mentioned

• . Conclusion When considering sterically demanding systems with haloaryl and boronic acids as substrates for the Suzuki–Miyaura coupling, many may consider 2,6-alkyl-disubstituted phenyl rings as a model sterically demanding system to test the robust nature of both metal catalyst and ligand, for example, much

Copper-catalyzed yne-allylic substitutions: concept and recent developments

• Shuang Yang and
• Xinqiang Fang

Beilstein J. Org. Chem. 2024, 20, 2739–2775, doi:10.3762/bjoc.20.232

• developments and illustrates the influences of copper salt, ligand, and substitution pattern of the substrate on the regioselectivity and stereoselectivity. Keywords: copper-catalysis; copper vinyl allenylidene intermediate; 1,3-enyne; 1,4-enyne; yne-allylic substitution; Introduction Copper is earth

• demonstrated that the terminal alkyne unit is crucial for the process and the reactions using different isomers all proceed via the same intermediate. Nonlinear relationship experiments proved that the active catalyst is a mono-copper complex containing one ligand. A catalytic cycle is proposed in which copper

• confirmed that a copper–ligand monomer complex exists in the mechanism through nonlinear relationship experiments and kinetic studies (Scheme 17). He et al. [68] developed the regio- and enantioselective monofluoroalkylation of yne-allylic esters using fluorinated malonates as the starting materials, giving