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

• carbazole, which is presented in this study (Scheme 1c). Results and Discussion Optimization of the reaction parameters To evaluate the feasibility of the reaction, we commenced our studies by exploring palladium-catalyzed regioselective ortho-C–H nitration of the N-pyridylcarbazole 1a as the model

• substrate, using silver nitrate as the nitrating agent (Table 1). After detailed optimization studies, we found that the treatment of 1a with AgNO3 in the presence of Pd2(dba)3 as the catalyst in 1,4-dioxane afforded the desired C1-nitrated product 2a in 69% isolated yield (Table 1, entry 1). Product 2a was

• of our method. Key mechanistic studies. Optimization studies.a Supporting Information Supporting Information File 9: Experiment details, characterization data, copy of NMR spectra of synthesized compounds, and single-crystal X-ray diffraction data. Supporting Information File 10: CIF file for 2a

Synthesis of the tetracyclic skeleton of Aspidosperma alkaloids via PET-initiated cationic radical-derived interrupted [2 + 2]/retro-Mannich reaction

• Ru-Dong Liu,
• Jian-Yu Long,
• Zhi-Lin Song,
• Zhen Yang and
• Zhong-Chao Zhang

Beilstein J. Org. Chem. 2025, 21, 2470–2478, doi:10.3762/bjoc.21.189

• proceeds via an unusual 1,3-C shift to afford M, i.e. through an interrupted [2 + 2] cyclization/retro-Mannich reaction. Results and Discussion Conditions optimization Our study commenced with the evaluation of the proposed PET-based tandem [2 + 2] cyclization/retro-Mannich reaction. We selected compound

The intramolecular stabilizing effects of O-benzoyl substituents as a driving force of the acid-promoted pyranoside-into-furanoside rearrangement

• Alexey G. Gerbst,
• Sofya P. Nikogosova,
• Darya A. Rastrepaeva,
• Dmitry A. Argunov,
• Vadim B. Krylov and
• Nikolay E. Nifantiev

Beilstein J. Org. Chem. 2025, 21, 2456–2464, doi:10.3762/bjoc.21.187

• determined by 1H NMR spectroscopy. (A) Conformers arising during the rotation around the C5–C6 bond in pyranosides. (B) Furanoside ring conformers of monosaccharide 2 in the pseudorotation diagram. The dashed colored circles denote the initial conformations taken for optimization. Solid colored circles

• colored circles denote the initial conformations taken for optimization. Solid colored circles correspond to obtained conformations. (C) Calculated Gibbs free energies for various conformers of monosaccharides 3 and 4. For conformers 4-a and 4-b, the optimal torsional angles ω1 and ω of the side chain are

Transformation of the cyclohexane ring to the cyclopentane fragment of biologically active compounds

• Natalya Akhmetdinova,
• Ilgiz Biktagirov and
• Liliya Kh. Faizullina

Beilstein J. Org. Chem. 2025, 21, 2416–2446, doi:10.3762/bjoc.21.185

• , cyclopentanone 234 and the Grob fragmentation product, enone 235, were isolated from the reaction mixture. Cyclopentanone 234 can be used in the synthesis of 7-ketologanin (236) after optimization of the transformation. The product of the Wagner–Meerwein rearrangement, cyclopentanone 234, was formed according to

The high potential of methyl laurate as a recyclable competitor to conventional toxic solvents in [3 + 2] cycloaddition reactions

• Ayhan Yıldırım and
• Mustafa Göker

Beilstein J. Org. Chem. 2025, 21, 2389–2415, doi:10.3762/bjoc.21.184

• the reaction medium after five minutes. e) The spectrum of the isolated product 3a. Molecular structures of parent compounds 1a–f, 2a–d and cycloadducts 3a–u. Endo and exo stereoisomeric approaches of nitrone 1a and maleimide 2a in [3 + 2] cycloaddition reaction. Optimization of the [3 + 2

Synthetic study toward vibralactone

• Liang Shi,
• Jiayi Song,
• Yiqing Li,
• Jia-Chen Li,
• Shuqi Li,
• Li Ren,
• Zhi-Yun Liu and
• Hong-Dong Hao

Beilstein J. Org. Chem. 2025, 21, 2376–2382, doi:10.3762/bjoc.21.182

• ][21]. Additionally, a series of vibralactone homodimers and oxime esters 10–12 were reported by the groups of Liu and Zhang, respectively [22][23]. Through modification of the primary hydroxy group, a structure-based optimization of vibralactone (6) was carried out by Liu and co-workers and yielded

Conformational effects on iodide binding: a comparative study of flexible and rigid carbazole macrocyclic analogs

• Guang-Wei Zhang,
• Yong Zhang,
• Le Shi,
• Chuang Gao,
• Hong-Yu Li and
• Lei Xue

Beilstein J. Org. Chem. 2025, 21, 2369–2375, doi:10.3762/bjoc.21.181

• . This further corroborates the decisive role of the macrocyclic architecture in the anion recognition process. Quantum chemical calculations were performed with the ORCA 5.0.3 software [29]. The geometry optimization was performed by using B3LYP with the def2-SVP basis set. As illustrated in the

Adaptive experimentation and optimization in organic chemistry

• Artur M. Schweidtmann and
• Philippe Schwaller

Beilstein J. Org. Chem. 2025, 21, 2367–2368, doi:10.3762/bjoc.21.180

• automation and artificial intelligence is creating unprecedented opportunities for accelerating chemical discovery and optimization [1][2]. This thematic issue explores how adaptive experimentation, automation, and human–AI synergy are reshaping organic chemistry research. Several key technological advances

• analyze experiments using machine learning optimization algorithms [5][6]. Together, these capabilities are dramatically increasing the speed and efficiency of chemical optimization with respect to economic and environmental objectives [7]. The contributions in this thematic issue showcase innovative

• approaches across multiple areas. Quijano Velasco et al. review recent advances in high-throughput automated chemical reaction platforms and machine learning algorithms for reaction optimization, showing how these approaches reduce experimentation time and human intervention [8]. They also discuss current

Recent advances in Norrish–Yang cyclization and dicarbonyl photoredox reactions for natural product synthesis

• Peng-Xi Luo,
• Jin-Xuan Yang,
• Shao-Min Fu and
• Bo Liu

Beilstein J. Org. Chem. 2025, 21, 2315–2333, doi:10.3762/bjoc.21.177

• ; and subsequent conversion of the ketone in 20 to the vinyl iodide in 21 – via hydrazone formation, lithium–halogen exchange, and final nucleophilic substitution – secured the Norrish–Yang cyclization precursor 22. Following systematic optimization of reaction conditions, irradiation of 22 with 100 W

• safety and controllability of the reaction, and at the same time, it is also conducive to the rapid optimization of reaction conditions and scale-up production. Finally, the Norrish–Yang reaction can utilize artificial intelligence to assist in designing reaction routes in the future, and through big

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

• nexus for the rational design and optimization of highly effective, selective homogeneous catalytic systems. In 2013, Barriault and co-workers demonstrated that strategic modulation of steric and electronic ligand parameters within gold(I)-catalyzed cyclization pathways enables the selective assembly of

• accelerating reaction optimization. Furthermore, expanding this concept to other reaction manifolds – such as electrocyclic processes and photoredox catalysis – may uncover new avenues for molecular innovation. The pursuit of pathway-economical synthesis represents a paradigm shift toward sustainable and

Pd-catalyzed dehydrogenative arylation of arylhydrazines to access non-symmetric azobenzenes, including tetra-ortho derivatives

• Loris Geminiani,
• Kathrin Junge,
• Matthias Beller and
• Jean-François Soulé

Beilstein J. Org. Chem. 2025, 21, 2234–2242, doi:10.3762/bjoc.21.170

• bromotoluene (Table 1, entries 5–8). For subsequent optimizations, we selected t-BuXPhos for practical reasons, as it is less sensitive to oxidative conditions. Further optimization revealed that Cs2CO3 is more efficient than NaH for this reaction (Table 1, entry 9). However, reactions conducted with a new

• formed to minimize steric clashes. Finally, reductive elimination leads to the formation of N,N-diarylhydrazine (D), which has been identified and characterized during the optimization process (see Supporting Information File 1 for details). In a second catalytic cycle, the N,N-diarylhydrazine (D

• palladium-catalyzed dehydrogenative C–N coupling with 2-bromotoluene (2a). Application to the synthesis of tetra-, tri or di-ortho-substituted azobenzenes via palladium-catalyzed dehydrogenative C–N coupling. aIsolated with 85–95% purity. Selected optimization of conditions for the synthesis of azobenzene

Thiadiazino-indole, thiadiazino-carbazole and benzothiadiazino-carbazole dioxides: synthesis, physicochemical and early ADME characterization of representatives of new tri-, tetra- and pentacyclic ring systems and their intermediates

• Gyöngyvér Pusztai,
• László Poszávácz,
• Anna Vincze,
• András Marton,
• Ahmed Qasim Abdulhussein,
• Judit Halász,
• András Dancsó,
• Gyula Simig,
• György Tibor Balogh and
• Balázs Volk

Beilstein J. Org. Chem. 2025, 21, 2220–2233, doi:10.3762/bjoc.21.169

• accelerated hepatic clearance (Clint) due to the metabolic sensitivity of this class of compounds. Thus, a strategy for additional lead optimization towards central nervous system drug candidates, commencing with compound 3e, is advised based on the preliminary ADME data. Conclusion The aforementioned

• -hexahydro[1,2,3]thiadiazino[6,5-a]carbazole 1,1-dioxide (3e) has been identified as a promising central nervous system drug candidate for pharmacological testing and eventual further structure–activity optimization. Experimental Compounds 5a, 5b, 7a–j, (E)-9a, (E)-9b, 3a–j, 10a, 10b are new and

Synthesis of triazolo- and tetrazolo-fused 1,4-benzodiazepines via one-pot Ugi–azide and Cu-free click reactions

• Xiaoming Ma,
• Zijie Gao,
• Jiawei Niu,
• Wentao Shao,
• Shenghu Yan,
• Sai Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2025, 21, 2202–2210, doi:10.3762/bjoc.21.167

• scaffolds in a highly efficient manner. It was found that brominated azides do not undergo lactamization under the current conditions which presents an opportunity for further optimization of reaction conditions to expand the scope. Experimental General procedure for synthesis of analogs 7 and 8 A solution

Multicomponent reactions IV

• Thomas J. J. Müller and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2025, 21, 2082–2084, doi:10.3762/bjoc.21.163

• optimization of promising lead structures has therefore inspired the development of powerful synthetic strategies. A glance at Web of Science reveals that one-pot methods and multicomponent reactions (MCRs) [1] have attracted steadily increasing attention within the scientific community over the past 25 years

Aryl iodane-induced cascade arylation–1,2-silyl shift–heterocyclization of propargylsilanes under copper catalysis

• Rasma Kroņkalne,
• Rūdolfs Beļaunieks,
• Armands Sebris,
• Anatoly Mishnev and
• Māris Turks

Beilstein J. Org. Chem. 2025, 21, 1984–1994, doi:10.3762/bjoc.21.154

• the reaction selectivity can be directed towards the formation of arylated dienes 10, which would directly contribute to our previous work [26]. Therefore, we performed optimization of the arylation conditions (Table 1) to improve the reaction selectivity towards the aryldiene 10a formation, indicated

• optimization see Supporting Information File 1. Next, we switched to internal N-nucleophiles. N-Nosylated starting material 7f under standard arylation conditions gave the 2-(1-(tert-butyldimethylsilyl)vinyl)-1-((4-nitrophenyl)sulfonyl)pyrrolidine (14) with a 56% yield. Most likely in this case sulfonamide N–H

• . aThe reaction was performed under modified conditions: I-2 (3.0 equiv), 20 h because under standard reaction conditions incomplete conversion was observed (with 48% recovered 16c). Reaction conditions optimization for the arylation of aliphatic chain-containing propargylsilane 7a. Aryldiene scope

Asymmetric total synthesis of tricyclic prostaglandin D2 metabolite methyl ester via oxidative radical cyclization

• Miao Xiao,
• Liuyang Pu,
• Qiaoli Shang,
• Lei Zhu and
• Jun Huang

Beilstein J. Org. Chem. 2025, 21, 1964–1972, doi:10.3762/bjoc.21.152

• ester 4. Optimization of conditions to convert diketone 15 into cyclopentanone 14.a Supporting Information Supporting Information File 42: Experimental procedures, characterization data and copies of 1H and 13C NMR spectra. Acknowledgements We thank Prof. Zhen Yang (Peking University) for helpful

Stereoselective electrochemical intramolecular imino-pinacol reaction: a straightforward entry to enantiopure piperazines

• Margherita Gazzotti,
• Fabrizio Medici,
• Valerio Chiroli,
• Laura Raimondi,
• Sergio Rossi and
• Maurizio Benaglia

Beilstein J. Org. Chem. 2025, 21, 1897–1908, doi:10.3762/bjoc.21.147

• reaction and a screening of reaction parameters such as solvents, electrodes materials, electrolytes, total charges, and concentrations of the reaction mixture was performed. All optimization studies were carried out using 0.5 mmol of 1a in the presence of methanesulfonic acid in an undivided cell (5 mL

• comprehensive optimization of the flow reaction conditions was carried out using the model substrate 1a systematically varying key parameters such as the working electrodes, the current intensity, the total charge, the flow rate, and the equivalents of the employed electrolyte. Following this in-depth screening

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

• . Plausible reaction mechanism. Optimization of reaction conditions.a Supporting Information Supporting Information File 24: Experimental section, characterization of synthesized compounds, and copies of spectra. Funding P.A.J. gratefully acknowledges the Chhatrapati Shahu Maharaj Research Training and

[3 + 2] Cycloaddition of thioformylium methylide with various arylidene-azolones in the synthesis of 7-thia-3-azaspiro[4.4]nonan-4-ones

• Daniil I. Rudik,
• Irina V. Tiushina,
• Anatoly I. Sokolov,
• Alexander Yu. Smirnov,
• Alexander R. Romanenko,
• Alexander A. Korlyukov,
• Andrey A. Mikhaylov and
• Mikhail S. Baranov

Beilstein J. Org. Chem. 2025, 21, 1791–1798, doi:10.3762/bjoc.21.141

• methylide with various arylidene-azolones. First, a series of various arylidene-azolones 1–5 were prepared (Scheme 2). All compounds were created in accordance with our previously published protocols [20][28][29]. Next, optimization of [3 + 2]-cycloaddition reaction condition was performed using derivatives

• . Optimization of the reaction conditionsa. Supporting Information Supporting Information File 22: Experimental part, X-ray data and copies of NMR spectra. Acknowledgements A.A. Korlyukov and A.R. Romanenko are grateful to Ministry of Science and Higher Education of the Russian Federation (Contract No. 075

Approaches to stereoselective 1,1'-glycosylation

• Daniele Zucchetta and
• Alla Zamyatina

Beilstein J. Org. Chem. 2025, 21, 1700–1718, doi:10.3762/bjoc.21.133

• glycosyl donor, the influence of remote protecting groups on donor reactivity and acceptor nucleophilicity should not be underestimated. This necessitates careful optimization of reaction conditions and the rational selection of compatible donor–acceptor pairs [77]. Protecting groups can also be used to

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

• engaged in the development of continuous-flow nitration systems. Keywords: continuous-flow; kinetics; nitration; optimization; scale up; Introduction Nitro compounds hold an extremely important position in the field of organic chemistry, mainly because they are easily obtainable and can be converted

• coexist with engineering bottlenecks requiring optimization in process safety and scale-up strategies. Contemporary research endeavors prioritize two synergistic pathways: (i) pioneering alternative nitration pathways via innovative chemical approaches, particularly through novel nitrating agent

• selection and strategic implementation of appropriate methodologies. This is particularly crucial given that the advantages of flow chemistry are not universally applicable across all nitration reactions. Consequently, the optimization of such processes must be carefully tailored to align with the specific

Structural analysis of stereoselective galactose pyruvylation toward the synthesis of bacterial capsular polysaccharides

• Tsun-Yi Chiang,
• Mei-Huei Lin,
• Chun-Wei Chang,
• Jinq-Chyi Lee and
• Cheng-Chung Wang

Beilstein J. Org. Chem. 2025, 21, 1671–1677, doi:10.3762/bjoc.21.131

• ), 1.15 EPS (2) and Rhizobium leguminosarum bv. viciae VF39 EPS (3). (a) Oak Ridge Thermal Ellipsoid Plot view of the X-ray crystal structure of pyruvylated galactose 6. (b) Hydrogen-bonding in the crystal structure of pyruvylated galactose 6. Synthesis of trisaccharide precursor 14. Optimization of

Influence of the cation in hypophosphite-mediated catalyst-free reductive amination

• Natalia Lebedeva,
• Fedor Kliuev,
• Olesya Zvereva,
• Klim Biriukov,
• Evgeniya Podyacheva,
• Maria Godovikova,
• Oleg I. Afanasyev and
• Denis Chusov

Beilstein J. Org. Chem. 2025, 21, 1661–1670, doi:10.3762/bjoc.21.130

• the approach where sodium hypophosphite was used as a reducing agent. The reactivity of LiH2PO2, KH2PO2, RbH2PO2, and CsH2PO2 in reductive amination was investigated for the first time (Scheme 1b). Results and Discussion At the initial step, optimization of reductive amination conditions on the

• benchmark reaction between cyclohexanone and morpholine was carried out (full optimization details are provided in Supporting Information File 1). The reaction could proceed in the presence of only H3PO2 furnishing the model product in 70% yield (Table 1, line 1) at 130 °C, for 4 h. To conduct the

• water led to the drop of the yield while comparably low amounts (less than 0.7 equiv) were favorable (see Table S2 in Supporting Information File 1). This influence could be explained by hindering of the iminium ion formation in the presence of water. Thus, the optimization of the reaction conditions

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

• reaction carried out in the presence of 5 mol % of NiSO4 gave not only dimer 4, but also the annulation product, compound 3a. Further optimization of the reaction conditions aimed at suppressing the formation of dimer 4 showed that nickel chelates exhibit enhanced selectivity in catalyzing the annulation

• reactions of indoles 9b,c with azirine 2a. Ni(II)- and Cu(I)-catalyzed reactions of indole 15 with azirine 2a. Optimization of 3a synthesis a. Supporting Information Deposition number 2402772 (compound 7) contains the supplementary crystallographic data for this paper. These data are provided free of

General method for the synthesis of enaminones via photocatalysis

• Paula Pérez-Ramos,
• Raquel G. Soengas and
• Humberto Rodríguez-Solla

Beilstein J. Org. Chem. 2025, 21, 1535–1543, doi:10.3762/bjoc.21.116

• photocatalyst. Examples of compounds with medicinal effects containing an enaminone structural moiety. Synthesis of enaminones. Substrate scope. Scale-up synthesis of enaminone 9a. Mechanistic studies. Proposed mechanism. Optimization of reaction conditions. Supporting Information Supporting Information File 6

• : Additional optimization details, mechanistic studies, experimental details, characterization data and NMR spectra for enaminones 9. Acknowledgements We would like to thank Prof. Jose Manuel Costa-Fernández for his help with the spectroscopic studies. Funding This work has received financial support from MCI