Palladium-catalyzed regioselective C1-selective nitration of carbazoles

• Vikash Kumar,
• Jyothis Dharaniyedath,
• Aiswarya T P,
• Sk Ariyan,
• Chitrothu Venkatesh and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2025, 21, 2479–2488, doi:10.3762/bjoc.21.190

• valuable platform for the selective functionalization of carbazoles, offering potential applications in optoelectronics, functional organic materials, and related areas while contributing to the advancement of C–H activation methodologies. Keywords: C–H activation; carbazole; catalysis; nitration

• addition to cross-coupling reactions, transition metal-catalyzed cyclization involving C–H activation approaches have also been reported [29][30][31][32][33][34][35][36]. Despite the significant advances in carbazole core constructions, the established protocols significantly lack access to selectively C1

• -decorated carbazoles. Consequently, functionalizing carbazoles via transition metal-catalyzed directed C–H activation becomes more attractive to introduce the desired functionality in a regioselective fashion. The C–H activation strategy is elegant in many ways since it utilizes nonfunctionalized or lesser

Catalytic enantioselective synthesis of selenium-containing atropisomers via C–Se bond formations

• Qi-Sen Gao,
• Zheng-Wei Wei and
• Zhi-Min Chen

Beilstein J. Org. Chem. 2025, 21, 2447–2455, doi:10.3762/bjoc.21.186

• axially chiral selenium-containing compounds by the formation of C–Se bonds is reviewed from three aspects. Review 1. Catalytic atroposelective synthesis of selenium-containing atropisomers by transition-metal-catalyzed C–H selenylation reactions Transition-metal-catalyzed enantioselective C–H activation

Comparative analysis of complanadine A total syntheses

• Reem Al-Ahmad and
• Mingji Dai

Beilstein J. Org. Chem. 2025, 21, 2334–2344, doi:10.3762/bjoc.21.178

• catalysis, C–H activation methods, biomimetic synthesis, classic rearrangements, skeletal editing logic, and others. In addition, these efforts enabled the identification of the potential cellular target of complanadine A, validation of its neurotrophic activity, establishment of preliminary structure

• ] cycloadditions. The Sarpong total synthesis of complanadine A enabled by a biomimetic strategy and C–H activation. The Tsukano total synthesis of complanadine A enabled by Diels–Alder cycloaddition, Heck cyclization, and directed C–H arylation. The Dai total synthesis of complanadine A using single-atom skeletal

Pathway economy in cyclization of 1,n-enynes

• Hezhen Han,
• Wenjie Mao,
• Bin Lin,
• Maosheng Cheng,
• Lu Yang and
• Yongxiang Liu

Beilstein J. Org. Chem. 2025, 21, 2260–2282, doi:10.3762/bjoc.21.173

• pathway changed significantly. The (E)-benzofulvene product 110 was exclusively generated through palladium-catalyzed C–H activation followed by a 5-exo-dig cyclization (Scheme 22, path b). This study established a general method for the divergent syntheses of phenylnaphthalenes and benzofulvenes from

Electrochemical cyclization of alkynes to construct five-membered nitrogen-heterocyclic rings

• Lifen Peng,
• Ting Wang,
• Zhiwen Yuan,
• Bin Li,
• Zilong Tang,
• Xirong Liu,
• Hui Li,
• Guofang Jiang,
• Chunling Zeng,
• Henry N. C. Wong and
• Xiao-Shui Peng

Beilstein J. Org. Chem. 2025, 21, 2173–2201, doi:10.3762/bjoc.21.166

• reversible C–H activation to give the six-membered intermediate C. Substitution of the acetate ligand in C by 3 caused the generation of complex D. The six-membered ruthenacycle E was then obtained by migratory insertion of acetylene into the Ru–C bond. Finally, reductive elimination of E formed the target

• for 6 h. The authors also proposed the reaction mechanism on basis of experimental results and previous literature [205][206]. Firstly, the ligand exchange between (R)-Rh1 and n-Bu4NOAc or 1-AdCO2H gave a chiral active catalyst A. The irreversible base-prompted C–H activation of A with 19a yielded a

• of 22 with Cu(OPiv)2 and the following anodic copper(II) oxidation provided copper(III) carboxylate intermediate B. Facile carboxylate-promoted C–H activation and ligand exchange with 23 formed the copper(III) species D, which underwent metalation/reductive elimination to generate intermediate E

Discovery of cytotoxic indolo[1,2-c]quinazoline derivatives through scaffold-based design

• Daniil V. Khabarov,
• Valeria A. Litvinova,
• Lyubov G. Dezhenkova,
• Dmitry N. Kaluzhny,
• Alexander S. Tikhomirov and
• Andrey E. Shchekotikhin

Beilstein J. Org. Chem. 2025, 21, 2062–2071, doi:10.3762/bjoc.21.161

• methodologies from traditional acylation/carbamoylation [9] to advanced Pd- or Rh-catalyzed C–H activation [10][11], FeIII–CuII/p-TSA–CuI catalyzed ring expansion/cyclization [12], electrochemical C–H/N–H functionalization [13], RhIII-catalyzed C–H amidation [14], etc. In contrast to chemical studies, a

Measuring the stereogenic remoteness in non-central chirality: a stereocontrol connectivity index for asymmetric reactions

• Ivan Keng Wee On,
• Yu Kun Choo,
• Sambhav Baid and
• Ye Zhu

Beilstein J. Org. Chem. 2025, 21, 1995–2006, doi:10.3762/bjoc.21.155

• atom is treated as a pseudo-tetrahedral center, with the metal regarded as one of the substituents. Accordingly, a C–H activation reaction that forms planar chiral ferrocenes [18] is assigned as [30] (Scheme 5A). For cyclophanes, if the bond formation or cleavage is on the stereogenic arene, the

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

• styrene, leading to the in situ generation of two valuable intermediates that act as dual synthons for the synthesis of 2,4- and 4-substituted quinolines. As part of our ongoing efforts to develop innovative C–C and C–H activation strategies for constructing nitrogen-containing heterocycles [55][56], we

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

Recent advances and future challenges in the bottom-up synthesis of azulene-embedded nanographenes

• Bartłomiej Pigulski

Beilstein J. Org. Chem. 2025, 21, 1272–1305, doi:10.3762/bjoc.21.99

• ]. Interestingly, initial attempts to convert 65 into 66 using various procedures for the palladium-catalysed C–H activation were unsuccessful, even when conducted at elevated temperatures. However, treatment of 65 with KOH in refluxing quinoline successfully yielded the desired PAH 66, albeit in a modest 15

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

• with α-aminoalkyl radicals generated from tertiary arylamines using photoredox catalysis (Scheme 13) [9]. In this system, Ir[dF(CF3)ppy]2(dtbbpy)PF6 was used as a photosensitizer to trigger the α-C–H activation of N,N-dimethylaniline, generating an alkyl radical under 30 W blue LED (454 nm) irradiation

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

• molecular architectures in pharmaceuticals, polymers, and agrochemicals. Despite advancements in directing group (DG) methodologies and computational approaches, predicting accurate regioselectivity in C–H activation poses significant difficulties due to the diversity and complexity of organic compounds

• . This study introduces a novel quantum mechanics-based computational workflow tailored for the regioselective prediction of C–H activation in the presence of DGs. Utilizing (semi-empirical) quantum calculations hierarchically, the workflow efficiently predicts outcomes by considering concerted

• reliable regioselectivity predictions that are essential for accelerating innovation in materials science and medicinal chemistry. Keywords: C–H activation; chemical synthesis planning; directing groups; quantum mechanics; regioselectivity prediction; Introduction The activation and functionalization of

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

Recent advances in controllable/divergent synthesis

• Jilei Cao,
• Leiyang Bai and
• Xuefeng Jiang

Beilstein J. Org. Chem. 2025, 21, 890–914, doi:10.3762/bjoc.21.73

• the σ-alkylpalladium intermediate Int-50. The intermediate Int-50 undergoes C–H activation to generate the spiro-palladacycle Int-51, which proceeds via two possible pathways: 1) Path a: oxidative addition/reductive elimination or 2) path b: transmetalation/reductive elimination giving rise to

• reactivity of cyclic diazo imides and mechanism [40]. Palladium-catalyzed annulation of prochiral N-arylphosphonamides with aromatic iodides [41]. Time-dependent enantiodivergent synthesis [42]. Time-controlled palladium-catalyzed divergent synthesis of silacycles via C–H activation [43]. Proposed mechanism

• accumulation of 51. Since 51 is highly stable and resistant to reaction with MeOH (k2R << k2S ≈ k1R), it can be obtained with high optical purity after an extended reaction time (10 hours) In 2023, Yang and Liang jointly reported a tetrasilane (ODCS)-based method for time-controlled, palladium-catalyzed C–H

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

• efficient and economical approach for molecular synthesis [40]. This strategy has been widely applied in synthetic chemistry, the pharmaceutical industry, and materials science. Over the past few decades, transition-metal-catalyzed C–H activation reactions have been widely developed. Late-stage C–H

• functionalization of highly complex and diverse molecules, such as those of pharmaceuticals and natural products, has provided new retrosynthetic disconnections for complex compounds, contributing to improved resource efficiency [41][42][43][44][45][46]. Recently, the merging of C–H activation and electrochemistry

• Cu-catalyzed electrochemical C–H activation strategy through C–H alkynylation of arylamides followed by electrooxidative cascade annulation (Figure 4) [48]. This reaction enables sustainable C–H functionalization by utilizing electricity as the terminal oxidant instead of stoichiometric amounts 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

Direct trifluoroethylation of carbonyl sulfoxonium ylides using hypervalent iodine compounds

• Radell Echemendía,
• Carlee A. Montgomery,
• Fabio Cuzzucoli,
• Antonio C. B. Burtoloso and
• Graham K. Murphy

Beilstein J. Org. Chem. 2024, 20, 3182–3190, doi:10.3762/bjoc.20.263

• ]. This synthetic potential has been demonstrated in a range of insertions into polar bonds [17][18][19][20], C−H activation transformations [21][22][23], and geminal difunctionalizations [24][25]. Within the literature, a broad array of classical methods describes the synthesis of sulfoxonium ylides [26

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

• carboxylate substrate and [Ru(p-cymene)Cl2]2. Subsequently, the Ru complex coordinates with the aniline substrate, followed by C–H activation to form a six-membered Ru species. The final product is generated through reductive elimination, releasing Ru(0), which is then reoxidized on the anode to regenerate

• mechanism. Initially, C–H activation occurs, resulting in the formation of a cyclometalated Ir(III) intermediate. Ligand exchange with the alkyne substrate, followed by migratory insertion, leads to the formation of a seven-membered 18-electron Ir(III) complex. This complex then undergoes reductive

pKalculator: A pK_a predictor for C–H bonds

• Rasmus M. Borup,
• Nicolai Ree and
• Jan H. Jensen

Beilstein J. Org. Chem. 2024, 20, 1614–1622, doi:10.3762/bjoc.20.144

• bond to create new connections has attracted increasing interest [1]. While past methods allowed for C–H transformations in simple molecules, recent synthetic protocols [2] enable selective C–H activation and diversification in larger molecules. This has, for example, attracted the pharmaceutical

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• on the arene were unsuccessful. Without substituents on the ring, aryl C–H activation and subsequent C–O bond formation occurred along with benzylic fluorination (7) (low efficiency). The presence of a p-methoxy group resulted in a switch in selectivity to acyloxylation 8’ as the major product. The

• with nucleophilic fluoride sources too (Figure 30) [77]. This process involved an initial quinoline-directed C–H activation by Pd(II), followed by oxidation to generate a Pd(IV)–fluoride complex capable of C–F reductive elimination to generate the primary benzyl fluoride. Under this protocol, eleven 8

Transition-metal-catalyst-free electroreductive alkene hydroarylation with aryl halides under visible-light irradiation

• Kosuke Yamamoto,
• Kazuhisa Arita,
• Masami Kuriyama and
• Osamu Onomura

Beilstein J. Org. Chem. 2024, 20, 1327–1333, doi:10.3762/bjoc.20.116

• versatile building blocks in organic syntheses. To achieve this transformation with high efficiency and predictable regioselectivity, numerous efforts have been made to develop transition-metal-catalyzed reactions based on a C–H activation strategy [1][2][3][4] or the reductive coupling of aryl halides with

Light on the sustainable preparation of aryl-cored dibromides

• Fabrizio Roncaglia,
• Alberto Ughetti,
• Nicola Porcelli,
• Biagio Anderlini,
• Andrea Severini and
• Luca Rigamonti

Beilstein J. Org. Chem. 2024, 20, 1076–1087, doi:10.3762/bjoc.20.95

• context of covalent organic frameworks (COFs) and metal-organic frameworks (MOFs), frequently assembled through imine linkages. While C–H activation through halogens presents clear technical advantages, it also brings forth concerns about the toxicity of halo compounds to both human health and the

Carbonylative synthesis and functionalization of indoles

• Alex De Salvo,
• Raffaella Mancuso and
• Xiao-Feng Wu

Beilstein J. Org. Chem. 2024, 20, 973–1000, doi:10.3762/bjoc.20.87

• bar of CO, in CH3CN at 160 °C. By this route, 29 examples were synthesized with isolated yields up to 91% (Scheme 27). One year later, Čarný and co-workers described a facile construction of the isoindolo[2,1-a]indol-6-one structure via a Pd-catalyzed aminocarbonylation and C–H activation reaction

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• shown by Molander and co-workers [77]. The synthesis of bridge heteroaryl 1,2,3-BCPs by a decarboxylative Minisci reaction was reported by Poole and co-workers [68]. The previously discussed C–H activation reported by MacMillan and co-workers (Scheme 2) was used to access a wide number of 1,2,3-BCPs [33

Regioselective quinazoline C2 modifications through the azide–tetrazole tautomeric equilibrium

• Dāgs Dāvis Līpiņš,
• Andris Jeminejs,
• Una Ušacka,
• Anatoly Mishnev,
• Māris Turks and
• Irina Novosjolova

Beilstein J. Org. Chem. 2024, 20, 675–683, doi:10.3762/bjoc.20.61

• reactions of substituted anilines VI, VII or N-arylamidines VIII are frequently employed for synthesizing C2-substituted quinazolines (Scheme 1), thereby influencing the spatial arrangement of the desired substituents [13][14]. Moreover, there have been recent advancements in efficient C–H activation