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

Tailored charge-neutral self-assembled L₂Zn₂ container for taming oxalate

• David Ocklenburg and
• David Van Craen

Beilstein J. Org. Chem. 2024, 20, 3007–3015, doi:10.3762/bjoc.20.250

• ready receptor preparation by metal complexation. The reason for the underrepresentation is the competitive nature and excellent ligand properties of oxalate which not only is associated with the aforementioned diseases but also poses a serious hazard for metal-driven self-assemblies because the dianion

• can easily replace ligand strands leading to a partial or full receptor decomposition. Herein, we present a charge-neutral zinc(II)-based metallocontainer which was tuned to contest oxalate as most competitive dicarboxylate. The dianion is bound in a 1:1 fashion with a binding constant of log K = 4.39

• this issue is to exchange the counteranions with less competitive ones, such as replacing tetrafluoroborate with tetrakis[3,5-bis(trifluoromethyl)phenyl]borate [64]. Alternatively, an emerging solution is the utilization of ligand–metal combinations that self-assemble into charge-neutral host systems

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

5th International Symposium on Synthesis and Catalysis (ISySyCat2023)

• Anthony J. Burke and
• Elisabete P. Carreiro

Beilstein J. Org. Chem. 2024, 20, 2704–2707, doi:10.3762/bjoc.20.227

• imidazolium ring formation. The resulting carbene was metalated at the C2 position with Au(I), Cu(I), and Ir(I), obtaining an L-shaped NHC ligand scaffold. Līpiņš et al. introduced a new method for synthesizing 4-azido-6,7-dimethoxy-2-alkyl/arylsulfonylquinazolines, which are key intermediates in the

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• complex, C(sp3)–H bonds underwent azidation with high chemoselectivity, even in the absence of a directing group. The proposed mechanism involves the formation of the active catalyst Mn(III)(N3) via ligand exchange, followed by anodic oxidation to a Mn(IV)(N3)2 complex. This high–valent Mn(IV) species

• product (Scheme 34). To date, only a few enantioselective reactions using metal catalysis and electrochemistry have been reported. Very recently, Ackermann and coworkers employed Co(OAc)2 as a catalyst and a salicyloxazoline derivative as a chiral ligand to achieve the electrochemical atroposelective C–H

• bonded to the nitrogen atom of the aniline substrate. The methodology showcases a broad scope for carboxylic acids and demonstrates multiple examples of LSF of pharmaceuticals and natural products. The proposed mechanism begins with the formation of Ru(II) diacetate through ligand exchange between the

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• (R)-VANOL ligand 115 was attained by column chromatography in 92%. In 2015, further development of the 2-aza-Cope rearrangement strategy was reported by Johnson [43]. This work expanded the scope of the reaction to β-formyl amides 119 under the conditions of dynamic kinetic resolution (DKR) by

Hydrogen-bond activation enables aziridination of unactivated olefins with simple iminoiodinanes

• Phong Thai,
• Lauv Patel,
• Diyasha Manna and
• David C. Powers

Beilstein J. Org. Chem. 2024, 20, 2305–2312, doi:10.3762/bjoc.20.197

• N-tert-butyl-α-phenylnitrone (PBN) afforded the aziridine product 3b in 60% NMR yield (Scheme 4d), suggesting a radical pathway was unlikely to be operative. An 1H NMR experiment was carried out to probe the speciation of 2a in HFIP, and we observed that 2a underwent reversible ligand exchange with

• iminoiodinane reacts directly with the olefin to generate a short-lived alkyl-bound iodinane 7 or iodonium species 8 (Scheme 4f). Ligand coupling from 7 or extrusion of iodobenzene from 8 would furnish a carbocation intermediate 9 which could undergo C–C bond rotation prior to ring closure to form the aziridine

Factors influencing the performance of organocatalysts immobilised on solid supports: A review

• Zsuzsanna Fehér,
• Dóra Richter,
• Gyula Dargó and
• József Kupai

Beilstein J. Org. Chem. 2024, 20, 2129–2142, doi:10.3762/bjoc.20.183

• catalyst closer to the support, impacting electronic properties and ligand conformation. With large catalyst molecules, the pores of an ordered mesoporous material being similar in size to the catalyst can create significant diffusion barriers as the catalyst attempts to enter the pores. As a result, the

Computational toolbox for the analysis of protein–glycan interactions

• Ferran Nieto-Fabregat,
• Maria Pia Lenza,
• Angela Marseglia,
• Cristina Di Carluccio,
• Antonio Molinaro,
• Alba Silipo and
• Roberta Marchetti

Beilstein J. Org. Chem. 2024, 20, 2084–2107, doi:10.3762/bjoc.20.180

• –ligand complexes, and analyse MD outcomes. Moreover, selected case studies have been reported to highlight the importance of computational tools in studying protein–glycan systems, revealing the capability of these tools to provide valuable insights into the binding kinetics, energetics, and structural

• state can be performed with the same tools described below in the protein–ligand interactions section. Computational tools to study proteins in the free state Knowledge on the three-dimensional structure of a protein is essential for understanding the functions and the dynamics of protein interactions

• study protein–ligand complexes Detailed investigations of protein–ligand interactions, combining experimental and computational methods, provide an indispensable basis to depict holistic pictures of molecular complexes allowing to modulate them at will. The computational approach involves i) predicting

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

• pathway enables the synthesis of 3,5-bis(biphenyl)-1-methyl pyrazole. To stabilize the catalyst, additional triphenylphosphane is added as a ligand during the Suzuki coupling. The resulting products fluoresce blue, with the five biaryl-substituted derivatives 113 showing the highest quantum yields of up

Development of a flow photochemical process for a π-Lewis acidic metal-catalyzed cyclization/radical addition sequence: in situ-generated 2-benzopyrylium as photoredox catalyst and reactive intermediate

• Masahiro Terada,
• Zen Iwasaki,
• Ryohei Yazaki,
• Shigenobu Umemiya and
• Jun Kikuchi

Beilstein J. Org. Chem. 2024, 20, 1973–1980, doi:10.3762/bjoc.20.173

• moderate yield (entry 1: 42%, cf. batch reaction: 76%). Lowering the reaction temperature to 25 °C reduced the yield (Table 1, entry 2: 35%), but decreasing the amount of the phosphine ligand from 20 mol % to 5 mol % markedly improved the yield (Table 1, entry 3: 53%). Even when the flow rate was increased