Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• toxicity [3][4][5][6][7]. Multicomponent reactions are one of the most effective methods to assemble multiple reagents, thus facilitating access to the target molecules more quickly, due to atom/step economy, short reaction times, and eco-friendly benefits. Combining multicomponent reactions with

Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

• discovery and medicine [4]. However, a lack of reliable synthetic methods for their preparation hindered the broader application of axially chiral compounds. In recent decades, there has been increased interest in the catalytic syntheses of axially chiral compounds by catalytic [5][6], especially

• organocatalyzed, methods [7][8][9][10][11]. Asymmetric organocatalysis offers efficient and environmentally benign access to numerous chiral compounds [12]. Therefore, an increasing number of researchers are now investigating the organocatalytic formation of compounds with axial stereogenic axes across various

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

• ), and appetite suppressants (e.g., phentermine) [6]. Phenethylamines can be produced via numerous different procedures [7]. One of the oldest methods involves the reduction of benzyl cyanide with H2 in liquid ammonia with Raney-Nickel catalyst at 130 °C, and high pressure [8]. Another known method is

• limited, since a NaBH4/transition metal salt system is mostly used to reduce nitroarenes [23][24][25][26]. One of the reported methods takes advantage of titanium(IV) isopropoxide as a catalyst to prepare varied β-phenethylamine analogues. Despite its simplicity, the reaction time is quite prolonged (from

• 18 to 20 hours), and this procedure is not used to prepare α-phenethylamines [27]. In view of the limitations associated with conventional methods, we report our findings on an improved approach for reducing β-nitrostyrenes to their corresponding substituted phenethylamines. We demonstrate that the

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

• leveraging on ML models to predict reaction outcomes and ML optimization algorithms, this new approach has demonstrated the ability to navigate the complex relationships between reaction variables and finding the global optimal conditions within a fewer number of experiments than with traditional methods [1

• tasks and reducing the overall process development lead time [3][4]. A standard workflow and general methodology for organic reaction optimization through ML methods is shown in Figure 1. The workflow comprises (i) careful design of experiments (DOE); (ii) reaction execution with commercial high

• analytics, and data processing methods to streamline repetitive experimental tasks, reduce manual intervention, and increase the rate of experimental execution in comparison to traditional manual experimentation. In conventional chemical synthesis, several sequential steps are typically undertaken

Chemical glycobiology

• Elisa Fadda,
• Rachel Hevey,
• Benjamin Schumann and
• Ulrika Westerlind

Beilstein J. Org. Chem. 2025, 21, 8–9, doi:10.3762/bjoc.21.2

• applicable to glycans. Today, the most amazing tools in genome engineering are used to great effect to disrupt or alter the glycan biosynthetic machinery, but they still cannot be used to, for instance, mutate one glycan into another in the same manner as nucleic acids can be mutated. Methods in molecular

• methods to make the glycosciences even more palatable to generalists. And we see a field that innovates. This thematic issue seeks to highlight the amazing breadth of contemporary chemical glycobiology. Dal Colle et al. investigate the determinants that influence the oligosaccharide yield in automated

• methods that underlie modern glycobioinformatics approaches [15]. Validation of glycoprotein structure is an important aspect of contemporary structural biology, and Dialpuri et al. present the Privateer database to allow for facile quality control of such structures [16]. Finally, Barillot et al. bridge

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

• ][27], as well as Friedel–Crafts [28] and Prins-type [29] reactions have been developed to date [2]. However, methods that enable access to the analogous acenaphthylene-fused heteroarenes are less common [30][31][32][33][34][35][36][37][38][39]. In one such study, Würthner and co-workers reported a Pd

• )Cl2·CH2Cl2 was used with 5 mol % catalyst loading (Table 1, entry 1). Next, we examined whether different thiophene-3-ylboronic esters could also be used under the same reaction conditions. A variety of borylation methods are capable of providing different boronic esters, such as pinacol [44][45][46

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

• 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

• photochemistry has introduced new ways of generating radicals like photoredox catalysis and via electron donor–acceptor (EDA) complexes [10][11][12][13]. These advances, coupled with modern electrochemical methods, chemical reactor engineering and light emitting diodes (LED), have eliminated the need for thermal

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

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

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

• ]-cycloaddition reaction between electron-poor 1,2-diaza-1,3-dienes and electron-poor alkenes in refluxing acetonitrile was reported leading to various substituted tetrahydropyridazines in 17–78% yields (Scheme 1c) [26][27]. Nevertheless, these methods are neither relevant for the synthesis of 1 nor appropriate

Surprising acidity for the methylene of 1,3-indenocorannulenes?

• Shi Liu,
• Märt Lõkov,
• Sofja Tshepelevitsh,
• Ivo Leito,
• Kim K. Baldridge and
• Jay S. Siegel

Beilstein J. Org. Chem. 2024, 20, 3144–3150, doi:10.3762/bjoc.20.260

• unforeseen new material designs (e.g., redox-active electrooptical materials). Methods pKa measurements in acetonitrile The experimental setup and methodology for the pKa determination of BFC and FIC in acetonitrile was essentially the same as described in detail in previous papers [12][13]. A brief

• , however, using them in reverse. The standard uncertainty estimates of the pKa values of FIC and BFC in DMSO are 0.8 pKa units. Synthesis Material used to measure the acidity of compounds BFC and FIC was prepared previously by methods reported in reference [9]. Computational methods The structural and

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

• combination of computational and experimental methods to study the electrocatalytic activity of the hydrogen evolution reaction (HER) catalyzed by free base 5,10,15-tris(pentafluorophenyl)corrole (98) [112]. Their work showed that using p-toluenesulfonic acid as the proton source, 98 was able to produce

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

• toward electrophiles [14][15][16][17][18][19]. Consequently, all reported asymmetric catalytic aldehyde allenylation methods are currently limited to metal/metalloid reagents bearing R2 substituents [21][22][23][24][25][26][27][28][29][30][31][32][33][34], except for the methods with

• became interested in investigating propargyltrichlorosilane for the development of asymmetric catalytic allenylation methods [46]. It is worthy of note that propargyltrichlorosilane is an easy-to-handle liquid and only produces innoxious NaCl and SiO2 as easy-to-separate inorganic byproducts upon

Extension of the π-system of monoaryl-substituted norbornadienes with acetylene bridges: influence on the photochemical conversion and storage of light energy

• Robin Schulte,
• Dustin Schade,
• Thomas Paululat,
• Till J. B. Zähringer,
• Christoph Kerzig and
• Heiko Ihmels

Beilstein J. Org. Chem. 2024, 20, 3061–3068, doi:10.3762/bjoc.20.254

• situation, the efficient and flexible conversion and storage of energy requires the variable combination of different, complementary storage systems, and as a consequence, the development of alternative methods for energy storage is still an important task to contribute to the mix of storage systems. One

Chemical structure metagenomics of microbial natural products: surveying nonribosomal peptides and beyond

• Thomas Ma and
• John Chu

Beilstein J. Org. Chem. 2024, 20, 3050–3060, doi:10.3762/bjoc.20.253

• recent years and new methods capable of exploring the natural product chemical space more broadly and more efficiently is in urgent need. Chemical structure metagenomics as one such method is the theme of this Perspective. It emphasizes a chemical-structure-centered viewpoint toward natural product

• the power of this viewpoint. It complements existing approaches to facilitate a broader and more efficient survey of the vast natural product chemical space that awaits our exploration. In BGF for microbial natural product discovery, the culture extract is fractionated using chromatographic methods

• unacceptably high rediscovery rates, because BGF has nearly exhausted the rather limited chemical space it can access. In light of BGF’s decreasing return-on-investment, scientists have developed new natural product discovery methods to tap into the microbial biosynthetic diversity of the “uncultured majority

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

• from the chiral nature of the CD molecule, and its behavior fits well with the theoretical consideration. As comprehensively described [32], CD-based rotaxanes are typically synthesized by two methods: (1) the end-capping method (route a1, a2) in which the formation of a pseudorotaxane structure first

• methods are more popular than the slipping method. However, this end-capping method must fulfill the following seven points to appropriately realize a rotaxane framework, and this causes several complexities (Figure 3): (1) The axle molecule must form a stable inclusion complex with CD, (2) the axle

• other synthetic methods: (1) the reaction can proceed on a 100 g scale in a 1 L flask and a 500 mL solution of water, sufficiently indicating the possibility of large-scale material applications; (2) the product contains only head-to-head structured [3]rotaxane, as confirmed by the X-ray crystal

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

• previously reported methods. Building block S2, based on dipropargylamine, is synthesized via a Schotten–Baumann reaction with benzoyl chloride, resulting in the flexible dialkyne backbone with a yield of 95%. The functionalization was envisioned to enhance the solubility of the ligand as we usually have

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

• Kharasch–Sosnovsky peroxidation became the basic universal platform for the development of peroxidation methods, with its great potential for rapid generation of complexity due to the ability to couple the resulting free radicals with a wide range of partners. This review discusses the recent advances in

• photoredox catalysis [26][27][28]. These methods allow selectivity to be controlled despite the presence of the complex cocktail of radical species generated by hydroperoxides under redox or homolysis conditions. The main challenge in selective radical peroxidation is the wide range of possible pathways

• ) and 2-methylcyclohexanone (17) using the Cu(I)/TBHP system (Scheme 9) [39]. α-Methyl-substituted peroxide 18 was obtained in higher yield (based on consumption of TBHP) than the peroxide from cyclohexanone 16, and was found to be more stable. Later, the methods for α-peroxidation of β-dicarbonyl

gem-Difluorovinyl and trifluorovinyl Michael acceptors in the synthesis of α,β-unsaturated fluorinated and nonfluorinated amides

• Monika Bilska-Markowska,
• Marcin Kaźmierczak,
• Wojciech Jankowski and
• Marcin Hoffmann

Beilstein J. Org. Chem. 2024, 20, 2946–2953, doi:10.3762/bjoc.20.247

• products. These highly stable compounds were isolated after purification on silica gel in good yields (Scheme 2) and characterized by spectroscopic methods. The reaction proceeded with very high Z-stereoselectivity (Scheme 2, compounds 9a–d). In the 19F NMR spectra of crude mixtures, only trace amounts of

• methods by the observed coupling constants J ≈ 6 Hz between vinylic fluorine atoms [41]. Due to the steric hindrance, these compounds did not serve as good Michael acceptors for the next step. Only elimination products 14a–d were obtained from trifluorinated amides 2a–d, showing good yields (Scheme 5). We

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

• when a minimal quantity of water was used as a solvent in the presence of a base. The ball-milling method efficiently simplified the reaction process because, in contrast to typical solution methods, it may realize product formation without being affected by the solubility of the substrate and other

• reaction that results in the formation of diaryl ethers. Diaryl ethers are important structural motifs in pharmaceuticals and agrochemicals due to their diverse biological activities. Since the 1950s, one of the most used methods for the synthesis of diaryl ethers involves the reaction of phenol with

• diaryliodonium salts. Recent advancements in this field have focused on the development of practically simple and scalable methods for the arylation of oxygen using diaryliodonium salts. By modifying the counter anions attached to the iodonium ion, the stability and reactivity of new symmetrical and

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

• corresponding sulfur-containing heteroarenes, only a few methods have been developed (Scheme 1). In 1988, Lee and co-workers reported the synthesis of SR-containing hydrazones in a two-step process (chlorination [65] then reaction with thiols) from readily available aldehyde-derived hydrazones [66]. Wang et al

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

• /benzoxazepine/benzothiazepine is very important. Due to the wide applications of pyrrole-fused heterocycles, very diverse approaches have been developed for their synthesis [28][29][30][31][32]. In recent years, multicomponent reactions (MCRs) have emerged as one of the most efficient and powerful methods to

• QS (quinine sulfate) (a); emission for 4a, 6c and QS (b); c = 75 ppm in ethanol and T = 298 K. Methods for the construction of pyrrole-fused heterocycles through I-MCR reactions. The model reaction of dibenzoxazepine, gem-diactivated olefin (2-benzylidenemalononitrile), and cyclohexyl isocyanide

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

• ] because of their easily modifiable dipeptide frameworks. Several methods exist for accessing PCPAs, such as the amination of 1-halo-1-alkynes [16][17], tandem reactions of α-imino esters with nucleophiles and electrophiles [18], and the nucleophilic addition of an acetylide to α-carbonylated N-acylimines

• various nucleophiles. This is because the imino carbon atom of 2 is also highly electrophilic, similar to DEMO [23][24][25]. This method offers an advantage over conventional methods as the N-acyl group can be modified by altering the acid amide. In this study, lithium acetylides were employed as

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

• ]pyrimidines using readily available derivatives of azaheterocycles as starting materials. As the last ones, we chose the reaction between 2-aminoimidazole and N-arylitaconimides or N-substituted maleimides, which can be analyzed by both classical synthetic and quantum DFT methods. The second problem solved in