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

• selection, a dispensing module for solids and liquids, a reaction module capable of heating and stirring, a sample preparation module, and a LC–MS characterization module (Figure 2d). The efficiency of the system has been demonstrated in three reactions types, namely Suzuki–Miyaura coupling, Buchwald

Synthesis, characterization, and photophysical properties of novel 9‑phenyl-9-phosphafluorene oxide derivatives

• Shuxian Qiu,
• Duan Dong,
• Jiahui Li,
• Huiting Wen,
• Jinpeng Li,
• Yu Yang,
• Shengxian Zhai and
• Xingyuan Gao

Beilstein J. Org. Chem. 2024, 20, 3299–3305, doi:10.3762/bjoc.20.274

• was achieved in 5 steps starting from commercially available 2-bromo-4-fluoro-1-nitrobenzene (1, Scheme 1 and Scheme 2). For the preparation of the key intermediate 5 (Scheme 1), self-coupling of 1 in the presence of copper followed by reduction of the nitro group generated diamine compound 3 (89

• room temperature. (a) PL spectra of the PhFlOP-based emitters 7 measured in toluene at room temperature. (b) PL spectra of 7-H measured in different solvents at room temperature. Preparation of key intermediate 5. Synthesis of PhFlOP-based molecules 7. Crystal data and structural parameters for 7-H

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

• free naphthol group in high yield (91%). We next turned our attention to the synthesis of benzo[j]fluoranthene 28, which is structurally related to 23, but with a free -OH group at a different position (Scheme 4). Our synthetic sequence commenced with the preparation of the known bromonaphthol 29 in

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

• first report from Zhdankin and co-workers in 1994, described the preparation of azidobenziodoxolone, ABX (I), a reagent widely used in oxidative azide transfer reactions [21]. Years later, Zhdankin’s group also reported the synthesis of amidobenziodoxolone (II) [14]. Other examples of N-containing

• a central theme of the work carried out by our research group in recent years, focusing on the formation of the S–N bond by applying the umpolung reactivity of HIRs, in particular in the preparation of sulfonamides and sulfonyl hydrazides [22][23]. In both approaches, a sulfonyl-containing

• formed by carboxylic acids, enhancing its versatility and effectiveness in drug design [27]. Traditional sulfonamide preparation involves combining sulfonyl chlorides and amines [25][28][29]. Despite the efficiency of traditional methods, challenges still remain, e.g., use of harsh conditions, like

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

• -protected Michael acceptor, derived from proline, allowed for preparation of compound 27 with a 35% yield in 4 hours without control of diastereoselectivity (dr = 1:1). Finally, to prove that the optimized reaction also works at a larger scale, the model reaction was carried out on a 2.2 mmol scale (Figure

Efficient synthesis of fluorinated triphenylenes with enhanced arene–perfluoroarene interactions in columnar mesophases

• Yang Chen,
• Jiao He,
• Hang Lin,
• Hai-Feng Wang,
• Ping Hu,
• Bi-Qin Wang,
• Ke-Qing Zhao and
• Bertrand Donnio

Beilstein J. Org. Chem. 2024, 20, 3263–3273, doi:10.3762/bjoc.20.270

• been studied in various solutions and thin film: G66 emitted green light in solution with an absolute photoluminescent quantum yield of ca. 33%. Results and Discussion Synthesis and characterization We have recently generalized a very efficient “palladium-free” synthesis for the preparation of a

• derivatives: the in situ prepared 2Li-BP5/6 was reacted with F5/6 to yield the symmetrical discotic dimers, G55/G66 respectively, in an average yield of 42–45% (Scheme 1). The reaction of 2Li-BP8 with F4 was also successfully tested, and allowed the preparation of the unsymmetrical discotic dimer G48

• . This documentation describes the methodologies employed for their preparation, the analytical techniques used to confirm their structures, and the data obtained confirming their identities [49]. Two additional compounds were synthesized to complete this study: the derivative with no alkoxy chains (F

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

• Anastasiya V. Agafonova Mikhail S. Novikov Alexander F. Khlebnikov Saint Petersburg State University, Institute of Chemistry, 7/9 Universitetskaya Naberezhnaya, St. Petersburg 199034, Russia 10.3762/bjoc.20.264 Abstract Methods for the preparation of 3-aryl-2H-azirine-2,2-dicarboxylic acids and

• their amides, esters, and azides by FeCl2-catalyzed isomerization of 3-aryl-5-chloroisoxazole-4-carbonyl chlorides into 3-aryl-2H-azirine-2,2-dicarbonyl dichlorides followed by their reaction with nucleophiles are reported. Two approaches to the preparation of 3-aryl-5-chloroisoxazole-4-carbonyl

• chlorides have been developed. Keywords: azirine-2,2-dicarboxamides; azirine-2,2-dicarboxylic acids; isomerization; isoxazoles; Introduction The isomerization of isoxazoles, containing a heteroatomic substituent at C5, to 2H-azirines is a powerful method for the preparation of 2H-azirine-2-carboxylic acid

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

• from the University of Waterloo (Department of Applied Math) for assisting in the preparation of the Julia script used to generate the reaction coordinate diagrams. Funding We would like to thank the São Paulo Research Foundation (FAPESP) for financial support (2023/02675-7) and in the form of

Synthesis of extended fluorinated tripeptides based on the tetrahydropyridazine scaffold

• Thierry Milcent,
• Pascal Retailleau,
• Benoit Crousse and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2024, 20, 3174–3181, doi:10.3762/bjoc.20.262

• chromatography. With dipeptides 7e and 7f stereoisomerically pure, we next focused our attention on the preparation of novel peptidic structures to perform some conformational analyses. Starting from the methyl ester 7, each diastereomer was engaged in a classical sequence of saponification in the presence of

• . Allylation of fluorinated hydrazones 3a–f to obtain 5a–f. Oxidation of hydrazines 5a–f to obtain hydrazones 6a–f. Intramolecular cyclization of compounds 6a–f to obtain tetrahydropyridazines 7a–f. Preparation of tripeptides 8e, 8e’, 8f, and 8f’. Yields refer to the yield over 2 steps. Supporting Information

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

• fluoride. Unsaturated alcohols gave moderate yields of racemic fluorinated tetrahydrofurans 26. Moderate yields were also reported for the fluorocyclisation of 3-butenoic acid (24) to form the fluorinated butyrolactone 28. The preparation of fluorinated oxazolines was reported in 2018 by Gilmour and co

• increased yields of cyclised product. Both 5- and 6-membered bromolactone products 69 and 70 were formed with 5-exo ring closure preferred. In addition to the synthesis of 5-chloromethyl-2-oxazolines 49, Li and co-workers reported the preparation of 5-bromomethyl-2-oxazolines 71 (Scheme 37) [48]. Treatment

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

• free-base) macrocycles have not been explored as much in terms of catalysis, even though they are starting compounds for the preparation of their metallated analogues that are commonly used as catalysts. In contrast with a calix[4]pyrrole macrocycle with four NHs (from four pyrrole units), a metal-free

• , Ballester and co-workers reported on the preparation of an octapyridinium-based water-soluble superaryl-extended calix[4]pyrrole molecular container and used it as a capsule for desymmetrization reactions [41], where the reported compound acts both as sequestering and supramolecular protecting group. All of

Enantioselective regiospecific addition of propargyltrichlorosilane to aldehydes catalyzed by biisoquinoline N,N’-dioxide

• Noble Brako,
• Sreerag Moorkkannur Narayanan,
• Amber Burns,
• Layla Auter,
• Valentino Cesiliano,
• Rajeev Prabhakar and
• Norito Takenaka

Beilstein J. Org. Chem. 2024, 20, 3069–3076, doi:10.3762/bjoc.20.255

• propargyltrichlorosilane without N,N-diisopropylethylamine and (b) with N,N-diisopropylethylamine. It includes Gibbs free energies (kcal/mol) and Mulliken charges (in parentheses). Metallotropic rearrangement and regioselectivity issues. Asymmetric catalytic allenylation of aldehydes. Selective preparation of

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

Tunable full-color dual-state (solution and solid) emission of push–pull molecules containing the 1-pyrindane moiety

• Anastasia I. Ershova,
• Sergey V. Fedoseev,
• Konstantin V. Lipin,
• Mikhail Yu. Ievlev,
• Oleg E. Nasakin and
• Oleg V. Ershov

Beilstein J. Org. Chem. 2024, 20, 3016–3025, doi:10.3762/bjoc.20.251

• the facile preparation of molecular libraries with an emphasis on skeletal diversity for the development of new push–pull molecules. Results and Discussion Synthesis and structure determination A two-step procedure was used to obtain the target compounds (Scheme 1). Cyclopenta[b]pyridine derivative 2

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

• connecting units for an easy ligand preparation (Figure 1b). The resulting compressed self-assembled host with a non-planar ligand backbone is the first charge-neutral metallocontainer able to bind oxalate forming a 1:1 host–guest complex with a binding constant of log K = 4.39 ± 0.04 in DMSO as highly

• preparation and host assembly. The synthesis adheres to a two-synthon approach which relies on the connection of two building blocks through a CuAAC click reaction (Scheme 1). Building block S1, the azide, is not modified in this work and the preparation is achieved with an overall yield of 43% via the

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

• -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

4,6-Diaryl-5,5-difluoro-1,3-dioxanes as chiral dopants for liquid crystal compositions

• Maurice Médebielle,
• Peer Kirsch,
• Jérémy Merad,
• Carolina von Essen,
• Clemens Kühn and
• Andreas Ruhl

Beilstein J. Org. Chem. 2024, 20, 2940–2945, doi:10.3762/bjoc.20.246

• still remain elusive and are not well understood [29]. Recently we have become interested in the preparation of racemic [30] anti- and highly enantioenriched 2,2-difluoro-1,3-diols [30][31][32] through an acylative double catalytic kinetic resolution (DoCKR) process [33]. While the 1,3-diol motif is

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

C–H Trifluoromethylthiolation of aldehyde hydrazones

• Victor Levet,
• Balu Ramesh,
• Congyang Wang and
• Tatiana Besset

Beilstein J. Org. Chem. 2024, 20, 2883–2890, doi:10.3762/bjoc.20.242

• using the synthetic potential of hydrazones in organic synthesis. Experimental General procedure for the preparation of trifluoromethylthiolated products 2–6: An oven-dried 10 mL reaction tube equipped with a stirring bar was charged with the hydrazone derivative (0.3 mmol, 1.0 equiv) and CH3CN (0.7 mL

Synthesis of pyrrole-fused dibenzoxazepine/dibenzothiazepine/triazolobenzodiazepine derivatives via isocyanide-based multicomponent reactions

• Marzieh Norouzi,
• Mohammad Taghi Nazeri,
• Ahmad Shaabani and
• Behrouz Notash

Beilstein J. Org. Chem. 2024, 20, 2870–2882, doi:10.3762/bjoc.20.241

• ), respectively. Preventive education for synthesizing triazolobenzodiazepine 6a–h Azides are highly reactive, toxic, explosive, and shock-sensitive chemicals that can be used under certain conditions. Special safety procedures must be followed during preparation, storage, handling, and disposal. TMSN3 is an

Multicomponent synthesis of α-branched amines using organozinc reagents generated from alkyl bromides

• Baptiste Leroux,
• Alexis Beaufils,
• Federico Banchini,
• Olivier Jackowski,
• Alejandro Perez-Luna,
• Fabrice Chemla,
• Marc Presset and
• Erwan Le Gall

Beilstein J. Org. Chem. 2024, 20, 2834–2839, doi:10.3762/bjoc.20.239

• stoichiometric amount of LiCl was essential for the efficiency of the subsequent three-component coupling with aldehydes and amines. A variety of primary, secondary, and tertiary organozinc reagents as well as secondary amines and aromatic aldehydes could be used for the straightforward preparation of α-branched

• amines. Interestingly, whereas previously reported work describing the preparation and reaction of organozinc iodides in acetonitrile showed higher reactivity of secondary organozinc reagents over primary ones, reactions in THF in the presence of LiCl led to opposite results, with higher reactivity of

• presence of LiCl in THF for the metalation of alkyl bromides at room temperature [19]. Besides, Huo described the insertion of zinc dust into alkyl bromides at 80 °C in DMA or DMF [20]. Despite the high synthetic interest in mixed organozinc compounds, their use in the preparation of α-branched amines

Synthesis of tricarbonylated propargylamine and conversion to 2,5-disubstituted oxazole-4-carboxylates

• Kento Iwai,
• Akari Hikasa,
• Kotaro Yoshioka,
• Shinki Tani,
• Kazuto Umezu and
• Nagatoshi Nishiwaki

Beilstein J. Org. Chem. 2024, 20, 2827–2833, doi:10.3762/bjoc.20.238

• (NAIs) [13][14][19][20][21][22]. To apply the latter method to the preparation of N,1,1-tricarbonylated propargylamines, the corresponding NAIs are necessary. However, the poor structural diversity of available NAIs limits the use of this method. For example, N,1-dicarbonylated NAIs derived from α-keto

• -4200 spectrometer equipped with an ATM detector. High-resolution mass spectra (HRMS) were obtained with a Bruker compact mass spectrometer APCI–TOF set at positive mode. The melting point was measured on an SRS-OptiMelt automated melting point system. Preparation of N,O-acetal 1 In a manner analogous

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

• each addition. In situ preparation of the [Tb.1·3Cu]3+ sensor. Solutions of 5 μM [Tb.1·3Cu]3+ were prepared by combining a DMSO stock solution of Tb.1 (100 μM) with 1 mM Cu(NO3)2·5H2O(aq). Solutions were then diluted with the appropriate amount of buffer (final concentration 10 mM Tris–HCl or 10 mM

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

• in Table 1). The optimal conditions found for product 4a also proved to be efficient for the preparation of its analogs 5 from N-arylitaconimides 3 (Scheme 1). Therefore, a broad range of variously substituted imidazo[1,2-a]pyrimidines was synthesized (Table 2). For the interaction of the

• candidates for further in vitro and in vivo testing as antifungal prodrugs. Experimental General procedure for preparation of N-R-7-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidine-5-carboxamides 4a–i: A mixture of 2-aminoimidazole hemisulfate (1, 0.66 g, 5 mmol), N-substituted maleimides 2a–i (5 mmol), sodium

• -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

Access to optically active tetrafluoroethylenated amines based on [1,3]-proton shift reaction

• Yuta Kabumoto,
• Eiichiro Yoshimoto,
• Bing Xiaohuan,
• Masato Morita,
• Motohiro Yasui,
• Shigeyuki Yamada and
• Tsutomu Konno

Beilstein J. Org. Chem. 2024, 20, 2776–2783, doi:10.3762/bjoc.20.233

• reports on the preparation of chiral molecules possessing a tetrafluoroethylene unit on an asymmetric carbon center in a high optical purity, and to the best of our knowledge, only the following have been published so far (Scheme 1). As a highly enantioselective synthesis, there has been a pioneering work

• diastereomers 12 and 13 are often easily separable, and each diastereomer of optically active alcohols or amines can be obtained with an excellent optical purity (reactions 3 and 4 in Scheme 1). To the best of our knowledge, these are the only four works for the preparation of optically active substances having

• ]-proton shift reaction of various tetrafluoroethylenated imines. Results and Discussion The preparation of substrates used in this study was as outlined in Scheme 3. Namely, the zinc reagent was prepared from commercially available 3,3,4,4-tetrafluoro-1-butene (18) [33] and reacted with various acid