Recent advances in synthetic approaches for bioactive cinnamic acid derivatives

• Betty A. Kustiana,
• Galuh Widiyarti and
• Teni Ernawati

Beilstein J. Org. Chem. 2025, 21, 1031–1086, doi:10.3762/bjoc.21.85

• been successfully done for this method. Similarly, Hou and co-workers (2022) also used CO2 to carry out an auto-tandem Cu-catalyzed carboxylation of styrenes via β-hydride elimination (208) (Scheme 60B) [104]. Impressively, several natural product-like compounds (e.g., 207) were successfully prepared

Recent total synthesis of natural products leveraging a strategy of enamide cyclization

• Chun-Yu Mi,
• Jia-Yuan Zhai and
• Xiao-Ming Zhang

Beilstein J. Org. Chem. 2025, 21, 999–1009, doi:10.3762/bjoc.21.81

• nucleophilic addition or substitution, the resulting iminium ions often undergo direct hydrolysis, preventing further use in a cascade nucleophilic addition. As a result, enamines are not ideal partners in tandem reactions for the synthesis of nitrogen-containing products. As analogues to enamines, the

• principles, tandem reactions or annulations can be designed to efficiently access N-heterocycles. As the enamides are also easily accessible via condensations, applications of these nitrogen-containing building blocks in the synthesis of N-heterocycles are synthetically straightforward. When applied properly

• , despite the potential for such a tandem reaction to provide a more efficient route to these complex structures. In 2016, Wang and co-workers indigenously designed and developed a cyclization/Pictet–Spengler reaction cascade, leveraging the nucleophilicity of the tertiary enamides and the electrophilicity

Silver(I) triflate-catalyzed post-Ugi synthesis of pyrazolodiazepines

• Muhammad Hasan,
• Anatoly A. Peshkov,
• Syed Anis Ali Shah,
• Andrey Belyaev,
• Chang-Keun Lim,
• Shunyi Wang and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2025, 21, 915–925, doi:10.3762/bjoc.21.74

• involving the Ugi reaction between arylglyoxals 1, benzylamines 2, o-azidobenzoic acid (3), and cyclohexyl isocyanide (4a), followed by a triphenylphosphine-promoted tandem Staudinger/aza-Wittig cyclization (Scheme 1a) [33]. The overall strategy was enabled by the presence of an azide group in the

• employed the U4CR of ortho-halogenated benzaldehydes 7, primary amines 2, 3-substituted propiolic acids 8, and isocyanides 4 to synthesize propargylamides 9. These propargylic Ugi adducts 9 were subsequently subjected to a Cu-catalyzed tandem azide–alkyne cycloaddition/Ullmann coupling resulting in the

Recent advances in controllable/divergent synthesis

• Jilei Cao,
• Leiyang Bai and
• Xuefeng Jiang

Beilstein J. Org. Chem. 2025, 21, 890–914, doi:10.3762/bjoc.21.73

• C(sp3)–C(sp3) coupling via distal stereocontrol, efficiently producing C3-alkylated pyrrolidines, while the nickel catalytic system afforded C2-alkylated pyrrolidines through a tandem alkene isomerization/hydroalkylation process. This method utilized readily accessible catalysts, chiral BOX ligands

• cycloaddition reactions with substituted furans as diene component to produce the corresponding epoxy-cycloaddition adducts. The authors developed an Ir/Sc tandem catalytic reaction to convert these adducts into polysubstituted 3-haloisoquinolines 99 in one pot. After obtaining isoquinoline compounds 99 with

• decarboxylative amination/hydroamination sequence [48]. Proposed mechanism of copper-catalyzed decarboxylative amination/hydroamination sequence [48]. Enantioselective chemodivergent three-component radical tandem reactions [49]. Substrate-controlled synthesis of indoles and 3H-indoles [52]. Controlled mono- and

Regioselective formal hydrocyanation of allenes: synthesis of β,γ-unsaturated nitriles with α-all-carbon quaternary centers

• Seeun Lim,
• Teresa Kim and
• Yunmi Lee

Beilstein J. Org. Chem. 2025, 21, 800–806, doi:10.3762/bjoc.21.63

• 98% yield. Ortho-bromoaryl-substituted nitrile 3m also underwent tandem amidation and copper-catalyzed cyclization, efficiently producing lactam 9 in a 98% yield. Scheme 7 illustrates a plausible reaction mechanism based on previous studies [34]. The process begins with the formation of NHC–copper

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

• temperatures, no specifically prepared solvents), one-pot, batch processes leading to tandem or cascade reactions, resource efficiency through the application of the 12 principles of Green Chemistry, and readily available starting materials such as waste materials from food production processes [1][2][3]. In

New tandem Ugi/intramolecular Diels–Alder reaction based on vinylfuran and 1,3-butadienylfuran derivatives

• Yuriy I. Horak,
• Roman Z. Lytvyn,
• Andrii R. Vakhula,
• Yuriy V. Homza,
• Nazariy T. Pokhodylo and
• Mykola D. Obushak

Beilstein J. Org. Chem. 2025, 21, 444–450, doi:10.3762/bjoc.21.31

• Yuriy I. Horak Roman Z. Lytvyn Andrii R. Vakhula Yuriy V. Homza Nazariy T. Pokhodylo Mykola D. Obushak Department of Organic Chemistry, Ivan Franko National University of Lviv, 6 Kyryla i Mefodiya St., Lviv 79005, Ukraine 10.3762/bjoc.21.31 Abstract A new tandem sequence involving the Ugi

• yields. The studied tandem Ugi and intramolecular Diels–Alder reactions allow high substituent variation in the named isoindoles. Keywords: 1,3-butadienylfuran; furo[2,3-f]isoindole; intramolecular Diels–Alder reaction; isoindole; one-pot; Ugi reaction; vinylfuran; Introduction Energy-saving and

• environmentally friendly synthetic strategies, especially one-pot multicomponent and tandem reactions, are key to modern organic and medicinal chemistry [1][2][3][4][5][6][7] and have proven to be successful in generating diverse heterocyclic scaffolds, as highlighted in a recent book [8]. Multicomponent

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

• nucleophile and electrophile) [5][6][7][8][9][10][11][12]. Crucially, enzymes organize their polarization – they achieve both components in tandem. Supramolecular chemists have made significant advances in cavity catalysis [13][14][15][16][17][18][19][20][21][22][23][24] – albeit slowly [25] – but have

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

• modular synthetic strategy involving the cascading assembly of the left THIQ segment. A concise modular synthetic process was developed to construct the substructure 14 of saframycin A (1), featuring copper(I)-catalyzed three-component coupling, and subsequent tandem 2,3-diaminobenzofuran formation

• coupling of alkyne 8, THIQ segment 9, and benzaldehyde would enable convergent assembly of the building blocks to produce 10 [43][44][45][46]. Removal of the cyclic acetal in 10 followed by Strecker-type conversion leading to an α-amino nitrile would enable tandem intramolecular cyclization with phenol to

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

• (KR) of the racemic ketimine ester, providing the same chiral product 35 with recovered enantioenriched starting material. Additionally, when a 1-naphthyl ester was used instead of a methyl ester at −10 °C, 1,4-addition followed by intramolecular tandem annulation generated the corresponding chiral

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

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

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

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

• -nitrogen atom. The second route involves the participation of an amino group which allows the formation of adducts 7 and 9 (routes A2 and B2). The intermediates formed then undergo subsequent tandem recyclization of succinimide/citraconimide fragments at the expense of one of the carbonyl groups and the

Applications of microscopy and small angle scattering techniques for the characterisation of supramolecular gels

• Connor R. M. MacDonald and
• Emily R. Draper

Beilstein J. Org. Chem. 2024, 20, 2608–2634, doi:10.3762/bjoc.20.220

• use of fluorescence probes should be used in tandem with CLSM. For example, Raeburn et al. showed that the addition of molecular rotors and fluorescent dyes affects the bulk network of self-assembled materials using rheology. The co-packing was observed to alter rheological properties of the materials

• opportunity for the directed tailoring of the nanostructure topology. To further characterise the structures of the self-assembled hollow cylinders, additional investigations are required. We discuss later how these structures can be further elucidated by using scattering and microscopy in tandem. SAS is also

• assemblies can give rise to microfibres with lengths in the order of tens of micrometres, all the way to centimetre scale assemblies [84]. Overcoming such restraints is possible by using several techniques in tandem to probe the entire length scale. Martin et al. previously investigated the hierarchical self

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

• employing a bulkier allyl-transfer reagent 116. They used a novel pre-formed chiral triborate catalyst 115 in tandem with a non-chiral Brønsted acid and expanded the scope to aliphatic homoallylic amines (Scheme 24). The new method established a scalable, chromatography-free purification protocol for the

• situ-generated N-acylquinolinium ions, catalysed by a tetrakis-triazole HBD catalyst [40]. Chiral phosphoric acid-catalysed aza-Cope rearrangement of in situ-formed N-α,α’-diphenyl-(α’’-allyl)methyliminium cations reported by Rueping et al. 2008 [41]. Tandem (R)-VANOL-triborate-catalysed asymmetric aza

Tandem diazotization/cyclization approach for the synthesis of a fused 1,2,3-triazinone-furazan/furoxan heterocyclic system

• Yuri A. Sidunets,
• Valeriya G. Melekhina and
• Leonid L. Fershtat

Beilstein J. Org. Chem. 2024, 20, 2342–2348, doi:10.3762/bjoc.20.200

• Federation 10.3762/bjoc.20.200 Abstract A straightforward protocol for the synthesis of a previously unknown [1,2,5]oxadiazolo[3,4-d][1,2,3]triazin-7(6H)-one heterocyclic system was developed. The described approach is based on tandem diazotization/azo coupling reactions of (1,2,5-oxadiazolyl)carboxamide

• a 1,2,3-triazin-4-one core. The proposed method is based on tandem diazotization/azo coupling reactions of the corresponding amides (Scheme 1). In addition, application perspectives of thus prepared heterocyclic entities as thermally stable components of functional organic materials or NO-donor drug

• synthesized via the reaction of the readily available 4-amino-3-(azidocarbonyl)-1,2,5-oxadiazole 2-oxide (3) with various amines, following a previously described procedure (see Supporting Information File 1 for details) [40][41]. Subsequently, we investigated the possibility of tandem diazotization/azo

Improved deconvolution of natural products’ protein targets using diagnostic ions from chemical proteomics linkers

• Andreas Wiest and
• Pavel Kielkowski

Beilstein J. Org. Chem. 2024, 20, 2323–2341, doi:10.3762/bjoc.20.199

• better identification of the modified peptides by search algorithms and second, if labeled with stable isotopes, it allows for quantification of the modified probe–peptide conjugates. Inspired by tandem mass spectrometry tags (TMT-tags) Makarov et al. have developed a ‘clickable’ 2,6-dimethylpiperidine

Selective hydrolysis of α-oxo ketene N,S-acetals in water: switchable aqueous synthesis of β-keto thioesters and β-keto amides

• Haifeng Yu,
• Wanting Zhang,
• Xuejing Cui,
• Zida Liu,
• Xifu Zhang and
• Xiaobo Zhao

Beilstein J. Org. Chem. 2024, 20, 2225–2233, doi:10.3762/bjoc.20.190

• ketene dithioacetals [67] or β-ethylthio-β-indolyl-substituted α,β-unsaturated ketones [68], the cyclocondensation reaction of β-ethylthio-β-indolyl-substituted α,β-unsaturated ketones with hydrazines/hydroxylamine [69][70][71] and the tandem [5C + 1C/1N]-cycloaromatization of α-alkenoyl ketene

O,S,Se-containing Biginelli products based on cyclic β-ketosulfone and their postfunctionalization

• Kateryna V. Dil and
• Vitalii A. Palchykov

Beilstein J. Org. Chem. 2024, 20, 2143–2151, doi:10.3762/bjoc.20.184

• Biginelli synthesis of dihydropyrimidinones/thiones/selenones via acetic acid or solvent-free Yb(OTf)3-catalyzed tandem reaction of β-ketosulfone (dihydro-2H-thiopyran-3(4H)-one-1,1-dioxide), an appropriate urea, and arylaldehyde has been developed. The reaction proceeds with high chemo- and

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

• interactions with the target were synthetized. After optimization of the reaction medium and of the concentration of reactants, and after setting up an analytical method relying on UPLC with tandem quadrupole detector, the on-target KTGS experiments were conducted. In a first set of experiments, a single

Ugi bisamides based on pyrrolyl-β-chlorovinylaldehyde and their unusual transformations

• Alexander V. Tsygankov,
• Vladyslav O. Vereshchak,
• Tetiana O. Savluk,
• Serhiy M. Desenko,
• Valeriia V. Ananieva,
• Oleksandr V. Buravov,
• Yana I. Sakhno,
• Svitlana V. Shishkina and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2024, 20, 1773–1784, doi:10.3762/bjoc.20.156

• component, after the formation of the expected Ugi bisamide products, subsequent post-transformations allow the synthesis of products of intramolecular cyclization [19][20][21][22] and/or products of a tandem combination of several reactions (Scheme 1) [22][23][24][25][26]. At the same time, the use of so

• used as acid components in tandem combinations of various multicomponent processes such as Ugi and Ugi, azido-Ugi and Ugi, Ugi and Passerini, Groebke–Blackburn–Bienaymé and Ugi, etc. [15][17][37][38]. The creation of hybrid molecules by using primary and post-modified Ugi products in combination with

• for two days and then heating the reaction mixture in a closed vessel at 80 °C for 3 hours (Scheme 5). This procedure led to the formation and isolation of the products 10d and 12e with yields which are similar to the tandem reaction. Using the example of bisamide 8c, it was found that changing the

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• demonstrate stereospecificity, again on predefined substrate classes. Radical fluorination methods offer an expansion to substrate scopes and rely on the use of more expensive fluorine-atom-transfer reagents. Finally, oxidative benzylic activation methods, often in tandem with enabling technologies, such as

Challenge N- versus O-six-membered annulation: FeCl₃-catalyzed synthesis of heterocyclic N,O-aminals

• Giacomo Mari,
• Lucia De Crescentini,
• Gianfranco Favi,
• Fabio Mantellini,
• Diego Olivieri and
• Stefania Santeusanio

Beilstein J. Org. Chem. 2024, 20, 1412–1420, doi:10.3762/bjoc.20.123

• represents an interesting example of auto-tandem catalysis in which FeCl3 promotes two subsequent reactions. For further confirmation to support our mechanistic hypothesis and in an attempt to switch the reaction toward the formation of hemiaminal 6a, we repeated the reaction of thiohydantoin 4j, (chosen as

• corroborate our mechanistic hypothesis related to the formation of both N,O-aminals and corresponding hemiaminals. In particular, the domino reaction that leads to the carbinolamines represents an interesting example of “auto-tandem catalysis” in which the FeCl3 catalyzes two different chemical

Sustainable tandem acylation/Diels–Alder reaction toward versatile tricyclic epoxyisoindole-7-carboxylic acids in renewable green solvents

• Ayhan Yıldırım

Beilstein J. Org. Chem. 2024, 20, 1308–1319, doi:10.3762/bjoc.20.114

• Ayhan Yildirim Department of Chemistry, Bursa Uludağ University, Bursa 16059, Turkey 10.3762/bjoc.20.114 Abstract Tandem Diels–Alder reactions are often used for the straightforward formation of complex natural compounds and the fused polycyclic systems contained in their precursors. In the

• prediction that their resources will run out in the near future has led 'green chemists' to explore solvents that can be derived from renewable resources and used effectively in various organic transformations. In this context, we have shown for the first time that the 100% atom-economical tandem Diels–Alder

• vegetable oils, the reaction was also carried out in a conventional organic solvent such as benzene, and the yield of the corresponding product is given in Table 1, entry 8. The epoxyisoindolinone product 2a formed by tandem intramolecular addition was easily separated from the reaction medium by