Copper-catalyzed domino cyclization of anilines and cyclobutanone oxime: a scalable and versatile route to spirotetrahydroquinoline derivatives

• Qingqing Jiang,
• Xinyi Lei,
• Pan Gao and
• Yu Yuan

Beilstein J. Org. Chem. 2025, 21, 749–754, doi:10.3762/bjoc.21.58

• under copper catalysis. After extensive optimization of the reaction parameters, the desired product 3aa was obtained in 92% yield under the following optimal conditions: the reaction between aniline (1a) and cyclobutanone oxime (2a) as the model system, hexane as the solvent, and copper(II

• spirotetrahydroquinoline (STHQ) scaffolds. Substrate scope. General reaction conditions: aniline 1 (0.2 mmol), 2 (0.4 mmol), and Cu(TFA)2 (0.04 mmol) in hexane (2.0 mmol) under air atmosphere, 12 h, 80 °C. Yields refer to isolated yields. Scale-up reaction.a Proposed mechanism. Optimization of reaction conditions.a

Asymmetric synthesis of fluorinated derivatives of aromatic and γ-branched amino acids via a chiral Ni(II) complex

• Maurizio Iannuzzi,
• Thomas Hohmann,
• Michael Dyrks,
• Kilian Haoues,
• Katarzyna Salamon-Krokosz and
• Beate Koksch

Beilstein J. Org. Chem. 2025, 21, 659–669, doi:10.3762/bjoc.21.52

• different fluorinated amino acids and target fluorinated amino acids described in the context of this work. Synthesis of fluorinated aromatic amino acids 2 and 3. a) Gram-scale synthesis of fluorinated alkyl iodide precursor 10; b) Synthesis of trifluorinated leucine analogs 12a and 12b. Optimization of the

• reaction conditions for the alkylation step using bromide 4. Optimization of the reaction conditions for the alkylation step using bromide 5. Optimization of the reaction conditions for the synthesis of the alkyl iodide 10. Optimization of the reaction conditions for the synthesis of alkylated complexes

Recent advances in allylation of chiral secondary alkylcopper species

• Minjae Kim,
• Gwanggyun Kim,
• Doyoon Kim,
• Jun Hee Lee and
• Seung Hwan Cho

Beilstein J. Org. Chem. 2025, 21, 639–658, doi:10.3762/bjoc.21.51

• investigation into whether such moderate activation strategies could facilitate copper-mediated coupling reactions of sterically demanding alkylboronic esters under mild conditions. After thorough reaction optimization, t-BuLi emerged as the superior activating agent, outperforming other organolithium compounds

• optimization revealed LiOt-Bu and diphenyl phosphate as the optimal metal alkoxide and leaving group, delivering the desired product 32 in high yield and high enantioselectivity at room temperature with only 2 mol % catalyst loading. The scope of this transformation proved to be remarkably broad. In addition

• approach focused on the diastereoselective formation of homoallylic boronic esters 36 through a carefully controlled sequence of hydrocupration and allylic substitution [39]. Through optimization studies, Yun found that CuCl with the Walphos ligand (L2) in Et2O provided optimal results, delivering the

Entry to 2-aminoprolines via electrochemical decarboxylative amidation of N‑acetylamino malonic acid monoesters

• Olesja Koleda,
• Janis Sadauskis,
• Darja Antonenko,
• Edvards Janis Treijs,
• Raivis Davis Steberis and
• Edgars Suna

Beilstein J. Org. Chem. 2025, 21, 630–638, doi:10.3762/bjoc.21.50

• -aminoproline derivatives 6. Optimization of anodic decarboxylation/amidation reaction. Supporting Information Supporting Information File 16: Detailed experimental procedures, analytical and spectroscopic data for the synthesized compounds, and copies of NMR spectra.

Photocatalyzed elaboration of antibody-based bioconjugates

• Marine Le Stum,
• Eugénie Romero and
• Gary A. Molander

Beilstein J. Org. Chem. 2025, 21, 616–629, doi:10.3762/bjoc.21.49

• stability, and/or a shorter ADC half-life [14]. Optimization of the drug/antibody ratio (DAR) and payload distribution/location thus becomes significant for ideal ADC design. Given the complexity of biological macromolecules, there are inherent limitations in terms of the types of reactions that can be used

• light control might also be improved using photochemical transformations. Importantly, optimization of bioconjugation reactions with technologies such as high-throughput experimentation has already been applied on antibodies [51]. Bioorthogonality Bioorthogonal chemistry has transformed our capability

Sequential two-step, one-pot microwave-assisted Urech synthesis of 5-monosubstituted hydantoins from L-amino acids in water

• Wei-Jin Chang,
• Sook Yee Liew,
• Thomas Kurz and
• Siow-Ping Tan

Beilstein J. Org. Chem. 2025, 21, 596–600, doi:10.3762/bjoc.21.46

• amino acids. Optimization of N-carbamylation of H1a. Supporting Information Supporting Information File 10: NMR and MS spectra of synthesized compounds. Funding The authors gratefully acknowledge the financial support from the TAR UMT Publication Incentive (FOAS/PS/86000-4923) provided by the Tunku

Formaldehyde surrogates in multicomponent reactions

• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Bernhard Westermann

Beilstein J. Org. Chem. 2025, 21, 564–595, doi:10.3762/bjoc.21.45

Study of the interaction of 2H-furo[3,2-b]pyran-2-ones with nitrogen-containing nucleophiles

• Constantine V. Milyutin,
• Andrey N. Komogortsev and
• Boris V. Lichitsky

Beilstein J. Org. Chem. 2025, 21, 556–563, doi:10.3762/bjoc.21.44

• conditions: 1c (1 mmol, 0.30 g), hydroxylamine hydrochloride (1.2 mmol, 0.08 g), EtOH (5 mL). Proposed reaction mechanism. Synthesis of product 13. Reaction conditions: 8o (1 mmol, 0.37 g), pivaloyl chloride (3 mmol, 0.36 g), MeCN (5 mL). Optimization of the reaction conditionsa. Supporting Information

Asymmetric synthesis of β-amino cyanoesters with contiguous tetrasubstituted carbon centers by halogen-bonding catalysis with chiral halonium salt

• Yasushi Yoshida,
• Maho Aono,
• Takashi Mino and
• Masami Sakamoto

Beilstein J. Org. Chem. 2025, 21, 547–555, doi:10.3762/bjoc.21.43

• , the reaction catalyzed by only 1 mol % of iodonium salt 9b provided the opposite diastereomer of 17a as the major product compared with that without a catalyst, which revealed the high catalytic activity of our catalyst. Further reaction conditions optimization was conducted using 9a as a catalyst

• chiral halonium salt. Next, the reaction temperature was optimized, and −40 °C was found to be optimal (Table 1, entries 7–9). Further optimization of the reaction conditions (amounts of potassium carbonate and pre-nucleophile, catalyst loading, and concentration) were conducted, and the reaction with

• optimization of the substituent on the 1-position of imines was conducted (Scheme 2). In most cases, the products were obtained in high yields with moderate to high enantioselectivities; the sterically less-hindered methyl-substituted substrate 7b was found to be better than the other substrates. The bulky

Vinylogous functionalization of 4-alkylidene-5-aminopyrazoles with methyl trifluoropyruvates

• Judit Hostalet-Romero,
• Laura Carceller-Ferrer,
• Gonzalo Blay,
• Amparo Sanz-Marco,
• José R. Pedro and
• Carlos Vila

Beilstein J. Org. Chem. 2025, 21, 533–540, doi:10.3762/bjoc.21.41

• , the reaction yielded compound 7 as the final product. Once the starting materials were synthesized, we focused our attention on the optimization of the reaction conditions. We chose the reaction between 4-cyclohexenyl-5-aminopyrazole (3aa) and methyl trifluoropyruvate (4a) for the optimization studies

• observed only racemic mixtures, likely due to the occurrence of a background reaction (details for asymmetric trials are provided in Supporting Information File 1). On the view of the results of the optimization process, we decided to study the reaction scope using the reaction conditions of entries 10 and

• chromatography. Diastereoisomeric ratio (dr) determined by 1H NMR of the crude reaction mixture. Plausible mechanism and X-ray structure of compound 5aca. Optimization of the reaction conditions.a Supporting Information Supporting Information File 14: Detailed experimental procedures, characterization data, and

Deep-blue emitting 9,10-bis(perfluorobenzyl)anthracene

• Long K. San,
• Sebastian Balser,
• Brian J. Reeves,
• Tyler T. Clikeman,
• Yu-Sheng Chen,
• Steven H. Strauss and
• Olga V. Boltalina

Beilstein J. Org. Chem. 2025, 21, 515–525, doi:10.3762/bjoc.21.39

• a relatively fast and efficient conversion into the desired products. Further optimization of this promising photochemical method is currently under way in our laboratory. Isolation and characterization Pure samples of 9,10-ANTH(BnF)2 and 9-ANTH(BnF) were isolated by HPLC (Figure S3, Supporting

Electrochemical synthesis of cyclic biaryl λ³-bromanes from 2,2’-dibromobiphenyls

• Andrejs Savkins and
• Igors Sokolovs

Beilstein J. Org. Chem. 2025, 21, 451–457, doi:10.3762/bjoc.21.32

• change of the anode material from GC to RVC or BDD (entries 8 and 9, Table 1), variation of electrolyte amount (entries 10 and 11) or altering of counter anions in the supporting electrolyte (entries 12 and 13; for complete optimization results, see Supporting Information File 1, Table S1). With the

• : Representative jp vs v0.5 slope values for oxidation of Martin’s bromane precursor 6 (ref. [17]). D: Plausible reaction mechanism. Optimization of electrochemical oxidation/cyclization conditions.a Supporting Information Crystallographic data for the structure reported in this paper have been deposited with the

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

• reagents (“cofactors”), they could perform non-biotic reactions, and even have potential for the design of novel active sites that could be transposed into new designer enzymes for optimization [388][389][390][391], since directed evolution requires initial activity to work from. Flexibility vs rigidity

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

• 40 has been proven to be the most efficient photocatalyst, promoting key transformations such as the aza-Henry reaction with 44 to give 45 under NIR light irradiation (Figure 6b). The reaction was found to critically depend on the presence of oxygen in the air for it to proceed. Through optimization

Molecular diversity of the reactions of MBH carbonates of isatins and various nucleophiles

• Zi-Ying Xiao,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2025, 21, 286–295, doi:10.3762/bjoc.21.21

• ), CH3CN (5.0 mL), rt, 2 h; yields refer to isolated yields. Proposed reaction mechanism for the various compounds. Optimization of reaction conditions.a Dimerization of MBH carbonates of isatins.a Supporting Information The crystallographic data of compounds 5a (CCDC 2390713), 5j (CCDC 2390714), 6e (CCDC

Synthesis and characterizations of highly luminescent 5-isopropoxybenzo[rst]pentaphene

• Islam S. Marae,
• Jingyun Tan,
• Rengo Yoshioka,
• Zakaria Ziadi,
• Eugene Khaskin,
• Serhii Vasylevskyi,
• Ryota Kabe,
• Xiushang Xu and
• Akimitsu Narita

Beilstein J. Org. Chem. 2025, 21, 270–276, doi:10.3762/bjoc.21.19

• byproduct in 7% yield along with BPP 2 in 55% yield (Table 1, entry 3). Further optimization of the reaction conditions by modifying the equivalent of SnCl2·2H2O and volume ratios iPrOH and H2SO4 afforded BPP-OiPr 3 in 55% yield (Table 1, entries 4 and 5). Additionally, the oxidation of BPP-OiPr 3 using

Synthesis of disulfides and 3-sulfenylchromones from sodium sulfinates catalyzed by TBAI

• Zhenlei Zhang,
• Ying Wang,
• Xingxing Pan,
• Manqi Zhang,
• Wei Zhao,
• Meng Li and
• Hao Zhang

Beilstein J. Org. Chem. 2025, 21, 253–261, doi:10.3762/bjoc.21.17

• 120 °C for 12 h; yield based on 3. Gram-scale synthesis of 2a and 4a and one-pot synthesis of 4a. Control experiments. Plausible reaction mechanism. Optimization of reaction conditions.a Supporting Information Supporting Information File 110: Experimental procedures, compound characterization data

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

• aryldifluoromethylation/cyclization reaction (for details about optimization conditions, please see Supporting Information File 1). We were delighted to find that when 2-fluorophenylacetic acid was employed as the fluorine source, a wide range of benzimidazole substrates were also compatible with this reaction. For

• . Optimization of reaction conditions.a Supporting Information Supporting Information File 102: Experimental procedures, product characterization, and copies of NMR spectra. Funding We are grateful to the Scientific Research Project of Hubei Education Department (T2020023 and Q20211402) and the open project of

Heteroannulations of cyanoacetamide-based MCR scaffolds utilizing formamide

• Marios Zingiridis,
• Danae Papachristodoulou,
• Despoina Menegaki,
• Konstantinos G. Froudas and
• Constantinos G. Neochoritis

Beilstein J. Org. Chem. 2025, 21, 217–225, doi:10.3762/bjoc.21.13

• activities, including antimalarial, antitumor, anthelmintic, antibacterial, antiasthmatic, and antiplatelet effects [61][62][63]. In particular, quinolinopyrimidine and pyrimidone derivatives have attracted a great interest due to their biological profile [64][65][66][67][68][69]. After some optimization, we

Facile one-pot reduction of β-nitrostyrenes to phenethylamines using sodium borohydride and copper(II) chloride

• Laura D’Andrea and
• Simon Jademyr

Beilstein J. Org. Chem. 2025, 21, 39–46, doi:10.3762/bjoc.21.4

• stirring with minor yield loss. Increasing the heating temperature up to 110 °C does not lead to increased product yields (for more information on the optimization process, see Supporting Information File 1, page S19). The use of diethylenetriamine (DETA) was also investigated to evaluate its impact on the

• optimization table, and ESI-MS spectra for the synthesis of 4b. Acknowledgements The authors acknowledge the Ph.D. thesis of L.D'A., titled "Design and Synthesis of beta-Arrestin-Biased 5HT2AR Agonists". Funding L.D’A. acknowledges the EU Horizon 2020, Innovative Training Network SAFER (765657). Conflict 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

• , the optimization of chemical reactions has been performed by manual experimentation guided by human intuition and through the design of experiments where reaction variables are modified one at a time to find the optimal conditions for a specific reaction outcome. Recently, a paradigm change in

• chemical reaction optimization has been enabled by advances in lab automation and the introduction of machine learning algorithms. Therein, multiple reaction variables can be synchronously optimized to obtain the optimal reaction conditions, requiring a shorter experimentation time and minimal human

• intervention. Herein, we review the currently used state-of-the-art high-throughput automated chemical reaction platforms and machine learning algorithms that drive the optimization of chemical reactions, highlighting the limitations and future opportunities of this new field of research. Keywords: autonomous

Reactivity of hypervalent iodine(III) reagents bearing a benzylamine with sulfenate salts

• Beatriz Dedeiras,
• Catarina S. Caldeira,
• José C. Cunha,
• Clara S. B. Gomes and
• M. Manuel B. Marques

Beilstein J. Org. Chem. 2024, 20, 3281–3289, doi:10.3762/bjoc.20.272

• ], HIR 2a might also be engaged in a radical mechanism contingent upon the medium or the species present. Analysis of data from optimization and scope experiments provided valuable insights into the reaction, leading to a plausible mechanistic proposal (Scheme 6). This suggestion is based on the

• : 4a (2 equiv), NaH (2.4 equiv), 2a, TEMPO (10 mol %), degassed DMF (0.055 M). NO – not observed. Mechanism proposed for sulfonamide 5, β-sulfinyl ester 4, disulfide 7, and sulfide 3 formations. The ionic steps are illustrated in green, whereas the radical steps appear in purple [35]. Optimization of

Giese-type alkylation of dehydroalanine derivatives via silane-mediated alkyl bromide activation

• Perry van der Heide,
• Michele Retini,
• Fabiola Fanini,
• Giovanni Piersanti,
• Francesco Secci,
• Daniele Mazzarella,
• Timothy Noël and
• Alberto Luridiana

Beilstein J. Org. Chem. 2024, 20, 3274–3280, doi:10.3762/bjoc.20.271

• )silane and a substoichiometric amount of (4-methoxyphenyl)(4-(trifluoromethyl)phenyl)methanone (BP l) (Table 1) [26][27]. The reaction was performed in batch, using a 390 nm Kessil UV-A lamp, stirring at 600 rpm overnight at 25 °C (see Supporting Information File 1 for a more detailed optimization). The

• observed in CH3CN (58% yield, 100% conv.; Table 1, entry 3). These conditions were further refined by adding of phosphate-buffered saline and decreasing the amount of (TMS)3SiH to 1.1 equiv, as no further increase in yield was noticed during the optimization. Similar to the reaction in deionized water, all

Synthesis of 2H-azirine-2,2-dicarboxylic acids and their derivatives

• Anastasiya V. Agafonova,
• Mikhail S. Novikov and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2024, 20, 3191–3197, doi:10.3762/bjoc.20.264

• -chloroisoxazole-4-carbonyl chlorides. Optimization of amide preparation. Supporting Information Supporting Information File 34: Experimental procedures and characterization data of new compounds. Acknowledgements In commemoration of the 300th anniversary of St Petersburg State University’s founding. This

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

• nudged elastic band climbing image (NEB-CI) method using Orca 5.0.1 at the PBE/def2-SVP D4 level of theory in the CPCM solvation model (see also section 4.2 in Supporting Information File 1) [51][52][53][54][55][56]. Both climbing images were subjected to transition state optimization and successfully

• met convergence criteria. Consistent with the PES scan outcome, the NEB-CI approach also indicated that the SN2 mechanistic proposal (Figure 2, path 2) dominates. Finally, for both mechanistic pathways, all intermediates and transition states were subjected to optimization and frequency calculations

• -mediated and SN2 reaction mechanisms. Ultimately, the nudged elastic band climbing image (NEB-CI) method predicted the SN2 pathway to be favoured, and transition state optimization showed this to possess a Gibbs free energy of activation of 24.3 kcal/mol. This report shows the ease with which sulfoxonium