Organocatalytic kinetic resolution of 1,5-dicarbonyl compounds through a retro-Michael reaction

• James Guevara-Pulido,
• Fernando González-Pérez,
• José M. Andrés and
• Rafael Pedrosa

Beilstein J. Org. Chem. 2025, 21, 473–482, doi:10.3762/bjoc.21.34

• organocatalytic synthesis of 2-cyclohexen-1-ones via a Michael/Michael/retro-Michael cascade reaction [31]. Our research has shown that the Jørgensen–Hayashi catalyst [32][33] is a highly promising organocatalyst, facilitating enantioselective Michael addition reactions with high yields and excellent levels of

Antibiofilm and cytotoxic metabolites from the entomopathogenic fungus Samsoniella aurantia

• Rita Toshe,
• Syeda J. Khalid,
• Blondelle Matio Kemkuignou,
• Esteban Charria-Girón,
• Paul Eckhardt,
• Birthe Sandargo,
• Kunlapat Nuchthien,
• J. Jennifer Luangsa-ard,
• Till Opatz,
• Hedda Schrey,
• Sherif S. Ebada and
• Marc Stadler

Beilstein J. Org. Chem. 2025, 21, 327–339, doi:10.3762/bjoc.21.23

• previously reported study investigating the biosynthesis of tenellin from Beauveria bassiana CBS110.25 [13], it was established that tenellin and a vast array of related metabolites could be synthesized through a cascade involving hybrid highly reducing polyketide synthase–non-ribosomal peptide synthetase

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

• can engage in electron-transfer mechanisms to enable radical cascade reactions under red-light irradiation (Scheme 9) [37]. These zinc(II)-based porphyrin catalysts operate via an oxidative quenching cycle, directly facilitating the transfer of an electron from the excited state of the porphyrin to

Streamlined modular synthesis of saframycin substructure via copper-catalyzed three-component assembly and gold-promoted 6-endo cyclization

• Asahi Kanno,
• Ryo Tanifuji,
• Satoshi Yoshida,
• Sota Sato,
• Saori Maki-Yonekura,
• Kiyofumi Takaba,
• Jungmin Kang,
• Kensuke Tono,
• Koji Yonekura and
• Hiroki Oguri

Beilstein J. Org. Chem. 2025, 21, 226–233, doi:10.3762/bjoc.21.14

• involvement of a fluorescent intermediate in the cascade synthetic process. Keywords: cascade reactions; copper-catalyzed three-component coupling; gold-mediated 6-endo hydroamination; tandem cyclizations; tetrahydroisoquinoline alkaloids; Introduction The bis-tetrahydroisoquinoline (THIQ) alkaloid family

• -fluorobenzene (see Scheme 2 and Supporting Information File 1 for details). Copper(I)-catalyzed three-component coupling reaction of alkyne 8, THIQ 9, and benzaldehyde, proceeded with exquisite control of regioselectivity to afford 10 in an excellent yield of 92% [43][44][45][46]. This efficient cascade

• measurements (Figures S20 to S25, Supporting Information File 1). A notable feature of this cascade process is the temporary protection of the C≡N triple bond, nitrile in the key intermediate 11, by the 2,3-diaminobenzofuran group. This facilitates the site-selective activation of the alkyne triple bond by the

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

• 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

• % CuCl2 catalyst was required, and anodic oxidation was employed instead of stoichiometric chemical oxidants. This cascade strategy is compatible with various substituted N-arylenamines 57 that bear electron-withdrawing and electron-donating groups, facilitating the production of quinoxaline scaffolds 59

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

• insights were outlined as well as cycloaddition and aza-Diels–Alder reactions were included. These strategies have gained attention due to their highly atom- and step-economy, one-step multi-bond forming, mild reaction conditions, low cost and easy handling. Keywords: cascade process; copper catalysis

• directly to the alkene, then reacts with the nucleophile to afford product 7. The regioselective 1,2-difunctionalization of allyl alcohol has been developed as a three-component cascade reaction using arenes and sulfonamides as nucleophiles to achieve arylation/hydroamination processes. The reaction

• reaction between the anhydride and the amine suggested the subsequent reaction with the ketone to give an imine intermediate XXIV. This latter can undergo intramolecular nucleophilic attack affording the quinazolinone derivative 26 (Scheme 20) [37]. Polysubstituted pyrroles 27 were obtained in a cascade

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

• ]. Hayashi realized an organocatalytic domino sequence that afforded axially chiral biaryls [24]. The transformation relied on an organocatalytic Michael/Henry cascade. The enamine-type Michael addition was catalyzed by the Hayashi–Jørgensen organocatalyst C7 (Scheme 6). Then, a series of one-pot reactions

• was carried out to provide the final biaryl products 17. In a related strategy, Hayashi´s team realized an organocatalytic Michael/aldol cascade leading to chiral dihydronaphthalene derivatives 20a–e [25]. Through a series of one-pot reactions, aromatization was achieved with concomitant central-to

• it with another aromatic moiety such as phenyl or 2-thiophenyl led to no product being formed. An organocatalytic atroposelective three-component cascade heteroannulation was done by Wang et al. [87]. It was a reaction of ketoesters 192, anilines 193, and cyclohexadiones 194 catalyzed by SPINOL

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

• stirred tank reactor (CSTR) cascade. The platform allowed to showcase the autonomous optimization to find the ideal reaction conditions for Suzuki–Miyaura and photoredox-catalyzed coupling reactions. A plug-and-play, continuous-flow chemical synthesis system (Figure 6a) was intelligently designed by

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

• , Ankara 06800, Türkiye 10.3762/bjoc.20.273 Abstract Acenaphthylene-fused heteroarenes with a variety of five- and six-membered heterocycles such as thiophene, furan, benzofuran, pyrazole, pyridine and pyrimidine were synthesized via an efficient Pd-catalyzed reaction cascade in good to high yields (45–90

• %). This cascade involves an initial Suzuki–Miyaura cross-coupling reaction between 1,8-dihalonaphthalenes and heteroarylboronic acids or esters, followed by an intramolecular C–H arylation under the same conditions to yield the final heterocyclic fluoranthene analogues. The method was further employed to

• reaction cascade starting from diarylalkynes 8, which involves indole formation/peri-C–H annulation and N-dealkylation reactions to afford acenaphthylene-fused indole products 9 (Scheme 1b) [41]. Recently, Takeuchi and co-workers reported an effective Ir-catalyzed [2 + 2 + 2] cycloaddition between 1,8

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• enantioselectivities (90–99% ee). This result could be attributed to the higher steric hindrance at the carbon atom of the imine. On the other hand, the reaction of 3-isothiocyanatooxindoles 4 and dienimines 9 afforded the cascade cycloadducts 10 in high yields (74–94%) and excellent diastereoselectivities (>20:1 dr

• under Brønsted base conditions. The authors claimed that the reactions to obtain the complex fused polycyclic diastereomeric products is proceeding through a cascade Michael addition–aza-Michael addition, however, they did not propose a plausible reaction pathway for the transformations. In order to

• -isothiocyanatooxindole. Cinchona-derived thiourea-catalyzed stereoselective (3 + 2)/(4 + 2) cascade reaction of α,β-unsaturated imines and 3-isothiocyanatooxindole. Enantioselective bifunctional squaramide-catalyzed formal [4 + 2] cycloaddition of malononitrile with benzofuran-derived azadienes. Bifunctional squaramide

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

• difference in HVI reagent used. In 2023, Du and co-workers reported a method for synthesizing 3-bromoindoles via a cascade oxidative cyclisation–halogenation encompassing oxidative C−N/C−Br bond formation, and utilising phenyliodine(III) diacetate (PIDA) in combination with LiBr in HFIP (Scheme 35) [54]. The

Synthesis of the 1,5-disubstituted tetrazole-methanesulfonylindole hybrid system via high-order multicomponent reaction

• Cesia M. Aguilar-Morales,
• América A. Frías-López,
• Nadia V. Emilio-Velázquez,
• Alejandro Islas-Jácome,
• Angelica Judith Granados-López,
• Jorge Gustavo Araujo-Huitrado,
• Yamilé López-Hernández,
• Hiram Hernández-López,
• Luis Chacón-García,
• Jesús Adrián López and
• Carlos J. Cortés-García

Beilstein J. Org. Chem. 2024, 20, 3077–3084, doi:10.3762/bjoc.20.256

• , 98160, México 10.3762/bjoc.20.256 Abstract A series of 1,5-disubstituted tetrazole-indole hybrids were synthesized via a high-order multicomponent reaction consisting of an Ugi-azide/Pd/Cu-catalyzed hetero-annulation cascade sequence. This operationally simple one-pot protocol allowed high bond-forming

• developed for synthesizing a small series of 1,5-disubstituted tetrazole-methanesulfonylindole hybrid compounds under mild reaction conditions. This strategy employs a cascade process consisting of a sequential Ugi-azide and Pd/Cu-catalyzed heteroannulation reactions, achieving low to moderate yields

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

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

• Cs2CO3 as shown in Scheme 1. The substrate scope exhibits that on using electron-deficient diaryliodonium salts as an arylating agent, α-fluoroacetamides 8 were obtained in moderate to good yields through a spontaneous arylation/deacylation cascade. The deacylation reaction is considered due to the

N-Glycosides of indigo, indirubin, and isoindigo: blue, red, and yellow sugars and their cancerostatic activity

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 2840–2869, doi:10.3762/bjoc.20.240

• in case of compound E-β-46b, the signaling cascade was investigated also for derivative E-β-46e. Important biochemical steps were again activation of caspase-3, downregulation of XIAP, upregulation of p53 and TRAIL receptor 2, STAT-3 dephosphorylation, and loss of mitochondrial membrane potential

• viability and in induction of apoptosis [50]. The presence of this compound results in downregulation of the caspase antagonistic proteins c-FLIP and XIAP via caspase-8 and caspase-3 in the (extrinsic) apoptosis cascade. Similarly as discussed above for the activity of 3-alkylideneoxindole-N-glycosides

Transition-metal-free decarbonylation–oxidation of 3-arylbenzofuran-2(3H)-ones: access to 2-hydroxybenzophenones

• Bhaskar B. Dhotare,
• Seema V. Kanojia,
• Chahna K. Sakhiya,
• Amey Wadawale and
• Dibakar Goswami

Beilstein J. Org. Chem. 2024, 20, 2655–2667, doi:10.3762/bjoc.20.223

• synthesis of E-o-hydroxystilbenes, albeit via a cascade hydrolyzation–decarboxylation reaction at a very high temperature (Figure 2c) [18]. However, a metal-free decarbonylation–oxidation method for benzofuranones is still unprecedented. The earlier report [2] on the Ni-catalyzed decarbonylation–oxidation

Base-promoted cascade recyclization of allomaltol derivatives containing an amide fragment into substituted 3-(1-hydroxyethylidene)tetronic acids

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

Beilstein J. Org. Chem. 2024, 20, 2585–2591, doi:10.3762/bjoc.20.217

Homogeneous continuous flow nitration of O-methylisouronium sulfate and its optimization by kinetic modeling

• Jiapeng Guo,
• Weike Su and
• An Su

Beilstein J. Org. Chem. 2024, 20, 2408–2420, doi:10.3762/bjoc.20.205

• of dicyclopentadiene (DCPD) in a continuous flow microreactor [15]. Where cyclopentadiene was the target intermediate formed by the thermal dissociation of dicyclopentadiene, cascade oligomerization was a side reaction to be avoided. Based on the deep understanding of the kinetic differences between

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• ]-rearrangement of ene-aldimines 149, catalysed by the BINOL-derived chiral phosphoric acid (CPA) (R)-151 (Scheme 31) [46]. DFT computational analysis suggested that the reaction proceeds via a complex cascade that involves the fragmentation of ene-aldimine 149 to form an imine methylene cation, which in turn

Catalysing (organo-)catalysis: Trends in the application of machine learning to enantioselective organocatalysis

• Stefan P. Schmid,
• Leon Schlosser,
• Frank Glorius and
• Kjell Jorner

Beilstein J. Org. Chem. 2024, 20, 2280–2304, doi:10.3762/bjoc.20.196

• [107] (Figure 11B). Werth and Sigman [127] investigated multiple nucleophilic additions to nitroalkenes, catalysed by bifunctional hydrogen bond donors, observing good correlations to new bi-functional donors, new nucleophiles, new electrophiles and even similar cascade-type reactions. In the authors

Efficacy of radical reactions of isocyanides with heteroatom radicals in organic synthesis

• Akiya Ogawa and
• Yuki Yamamoto

Beilstein J. Org. Chem. 2024, 20, 2114–2128, doi:10.3762/bjoc.20.182

• (R = EWG-C6H4, E = PhS and PhTe) in moderate to high yields [30]. Very few examples of intermolecular cascade reactions with imidoyl radicals as key intermediates have been reported. The intermolecular cascade reaction of diselenide, electron-deficient acetylene, and isocyanide under photoirradiation

• quinoxaline synthesis was reported to proceed by irradiation with visible light in the presence of dibenzylamine ((PhCH2)2NH, MeCN, rt, blue LED) [64]. This reaction involves a visible-light-induced single electron transfer (SET) process. An efficient radical cascade cyclization has also been reported, in

From perfluoroalkyl aryl sulfoxides to ortho thioethers

• Yang Li,
• Guillaume Dagousset,
• Emmanuel Magnier and
• Bruce Pégot

Beilstein J. Org. Chem. 2024, 20, 2108–2113, doi:10.3762/bjoc.20.181

• study, many research groups described a strategy for ortho-C–H functionalization of aryl sulfoxides with various nucleophiles via a cascade reaction of interrupted Pummerer reaction/sigmatropic rearrangement (Scheme 1a) [6][7][8][9][10][11]. A large range of nucleophiles, such as phenols [12][13][14][15

Diastereoselective synthesis of highly substituted cyclohexanones and tetrahydrochromene-4-ones via conjugate addition of curcumins to arylidenemalonates

• Deepa Nair,
• Abhishek Tiwari,
• Banamali Laha and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2024, 20, 2016–2023, doi:10.3762/bjoc.20.177

• Deepa Nair Abhishek Tiwari Banamali Laha Irishi N. N. Namboothiri Department of Chemistry, Indian Institute of Technology Bombay, Mumbai, 400 076, India 10.3762/bjoc.20.177 Abstract A cascade inter–intramolecular double Michael strategy for the synthesis of highly functionalized cyclohexanones

• treatment of Alzheimer's disease [3][4]. Likewise, RL91 and BHMPC are active for selective cell growth inhibition of the resistant lines (Figure 1) [5][6]. Their synthesis mainly involves a cascade Michael–aldol reaction between enones and suitable Michael donors such as β-ketosulfones, β-diketones, or

• starting materials for cascade/domino reactions. Curcumin is the key component present in turmeric and is responsible for its various biological activities. Turmeric has been used in many forms for potential health benefits and as a traditional spice for centuries [11]. Curcumin exhibits diverse biological

Solvent-dependent chemoselective synthesis of different isoquinolinones mediated by the hypervalent iodine(III) reagent PISA

• Ze-Nan Hu,
• Yan-Hui Wang,
• Jia-Bing Wu,
• Ze Chen,
• Dou Hong and
• Chi Zhang

Beilstein J. Org. Chem. 2024, 20, 1914–1921, doi:10.3762/bjoc.20.167

• –intramolecular cyclization cascade with excellent chemoselectivity in aqueous CH3CN [25]. Herein, as part of our continuing studies of heterocyclic scaffold synthesis mediated by hypervalent iodine reagents, we present the solvent-dependent chemoselective synthesis of a series of isoquinolinones mediated by PISA

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• approach offers several advantages since multiple bond formation, synthetic transformation and heterocyclic construction can be conducted in a single reactor [56]. Novel scaffolds derived from the GBB products have been successfully constructed through three types of one-pot synthesis, namely cascade

• /domino reaction, one-pot stepwise synthesis and multicomponent reaction. In the one-pot cascade reaction, the complexity of heterocycles was achieved due to the presence of functional groups formed in the GBB reaction which allow further reactions to occur. In the case of one-pot stepwise synthesis, the

• Ganesher [57] reported the one-pot cascade synthesis of indole-imidazo[1,2,a]pyridine hybrids 61 (Scheme 23). In this study, the convertible isocyanide 1-isocyano-2-(2,2-dimethoxyethyl)benzene (59, Kobayashi–Wessjohann isocyanide) was utilized as one of the precursors in the GBB reaction. The acetal