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

• 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

• 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

Light-enabled intramolecular [2 + 2] cycloaddition via photoactivation of simple alkenylboronic esters

• Lewis McGhie,
• Hannah M. Kortman,
• Jenna Rumpf,
• Peter H. Seeberger and
• John J. Molloy

Beilstein J. Org. Chem. 2025, 21, 854–863, doi:10.3762/bjoc.21.69

• , and control reactions support sensitization, enabling an intramolecular [2 + 2] cycloaddition to be realized accessing 3D bicyclic fragments containing a boron handle. Keywords: boron; catalysis; [2 + 2] cycloaddition; energy transfer; photochemistry; Introduction The strategic use of a photon to

• reactivity in EnT catalysis has also been intensively pursued (Figure 1B). The controlled geometric isomerization of boron-containing conjugated dienes [42], styrenes [43][44][45] and β-boryl acrylates [46][47] has been established with great effect, while elegant [2 + 2] cycloaddition strategies to readily

• . Herein, we demonstrate the sensitization of alkenylboronates to enable efficient intramolecular [2 + 2] cycloaddition using high energy photosensitizers (Figure 1C). Sensitization was quickly established and explored through the use of alkene scrambling (geometrical isomerization) reaction probes, to

New advances in asymmetric organocatalysis II

• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 766–769, doi:10.3762/bjoc.21.60

• cycloaddition reactions [1][2][3][4]. The history of scientific discoveries, however, is rarely defined by single specific dates that can unambiguously be connected to the discoveries. Instead, the chronology often seems to be quite convoluted but also ultimately more interesting, as can also be seen for

• organocatalytic cycloaddition reactions of unsaturated imines. A broad variety of activation modes, as well as catalyst structures, was covered and found to be useful in affording a diverse array of chiral N-heterocycles [27]. In my group, we recently became interested in atroposelective catalytic syntheses

Development and mechanistic studies of calcium–BINOL phosphate-catalyzed hydrocyanation of hydrazones

• Carola Tortora,
• Christian A. Fischer,
• Sascha Kohlbauer,
• Alexandru Zamfir,
• Gerd M. Ballmann,
• Jürgen Pahl,
• Sjoerd Harder and
• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2025, 21, 755–765, doi:10.3762/bjoc.21.59

• through calcium catalysis [8][9][10]. Asymmetric synthesis has also been achieved via, e.g., 1,4-addition and [3 + 2] cycloaddition of 3-tetrasubstituted oxindoles with a calcium Pybox catalyst [11][12], or through enantioselective Friedel–Crafts and carbonyl–ene reactions [13]. Since the pioneering

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

• ] cycloaddition step that ends with aromatization through a 1,3-H shift (Scheme 31) [84][85]. These compounds are highly relevant biological scaffolds for drug discovery [84]. In general, this reaction works very well with a wide variety of Lewis acids (as Sc(OTf)3 and MgCl2) and Brønsted acids (e.g., NH4Cl and

• methyl isocyanide (TosMIC), an aldehyde, and an amine is a well-known procedure for synthesizing polysubstituted imidazoles 43 (Scheme 38). The reaction involves a cycloaddition between the isocyanide and the imine generated in situ, ending with the hydrolysis of the tosyl group. This methodology works

• well for a wide variety of solvents and under mild basic conditions, since the solubility of the reagents and ease of product isolation are the factors that govern the choice. Sisko et al. used DMF/K2CO3 as the best conditions to carry out the cycloaddition of a wide variety of amines, aldehydes, and

Unprecedented visible light-initiated topochemical [2 + 2] cycloaddition in a functionalized bimane dye

• Metodej Dvoracek,
• Brendan Twamley,
• Mathias O. Senge and
• Mikhail A. Filatov

Beilstein J. Org. Chem. 2025, 21, 500–509, doi:10.3762/bjoc.21.37

• E. M. Kosower in 1978. In this study, we report the topochemical cycloaddition of diethyl 2,6-dichloro-1,7-dioxo-1H,7H-pyrazolo[1,2-a]pyrazole-3,5-dicarboxylate (Cl2B), initiated by visible light. Crystal structure analysis confirmed that the reactive double bonds are parallel and coplanar, in line

• with the Schmidt criteria for topochemical cycloaddition. Additionally, two other bimane derivatives with different substitution patterns were synthesized and investigated. Our findings suggest that functionalizing bimanes to redshift their absorption maxima into the visible-light spectrum provides a

• promising strategy for synthesizing substituted cyclobutanes without the need for ultraviolet irradiation. Keywords: bimane; [2 + 2] cycloaddition; fluorescence; topochemical polymerization; X-ray crystallography; Introduction Topochemical polymerizations refer to polymerization reactions occurring in the

Photomechanochemistry: harnessing mechanical forces to enhance photochemical reactions

• Francesco Mele,
• Ana M. Constantin,
• Andrea Porcheddu,
• Raimondo Maggi,
• Giovanni Maestri,
• Nicola Della Ca’ and
• Luca Capaldo

Beilstein J. Org. Chem. 2025, 21, 458–472, doi:10.3762/bjoc.21.33

• alignment within the crystal drives the reaction. For example, in 2008, Vittal et al. [62] designed a mechanochemical strategy to align the C=C bonds of 4,4'-bipyridylethylene (bpe, 1.1) molecules to drive efficient [2 + 2] cycloaddition and give the corresponding cyclobutanes (1.2). This approach relied on

• are crucial for product formation. Lastly, the author noted that the inclusion of acetonitrile as a LAG agent enabled the transformation even without the presence of a photocatalyst [72][74]. In 2023, Braunschweig and co-workers reported the photomechanochemical [2 + 2] cycloaddition of acenaphthylene

• + 2] cycloaddition (Scheme 11). Regarding the experimental setup, the authors adapted a commercially available ball mill, by introducing a custom-made stainless steel safety shield to minimize unwanted light leakage. The interior surface of the shield is somewhat reflective. A hole in the milling

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

• diaryl λ3-bromanes under remarkably mild conditions with subsequent applications of the in situ-generated arynes in cycloaddition reactions [3], meta-selective reactions with oxygen and nitrogen nucleophiles [4][5], regiodivergent meta or ortho-alkynylations [6], and regioselective (di)halogenation [7

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

• reaction and Diels–Alder [4 + 2] cycloaddition based on vinylfuran and 1,3-butadienylfuran derivatives was designed and studied. It was found that in the case of 3-(furan-2-yl)acrylaldehyde, a one-pot Ugi reaction and intramolecular Diels–Alder vinylarene (IMDAV) reaction leads to the formation of the

• -3aH-furo[2,3-f]isoindole core in excellent yields. Under the same conditions, the (2E,4E)-5-(furan-2-yl)penta-2,4-dienal gives an Ugi adduct that undergoes the IMDA reaction without involving the furan core. The cycloaddition leads to the formation of 2,3,3a,4,5,7a-hexahydro-1H-isoindoles in high

• [11][12][13]. Advancements in one-pot syntheses, like combining the Ugi reaction with other methods [14][15][16][17][18], for example, the Huisgen cycloaddition, have led to the creation of unique [1,2,3]triazolo[1,5-a]pyrazine derivatives [19]. Tandem reactions are particularly valued for their atom

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

• very different to that of the above mentioned reactions of MBH nitriles and formates of isatins. It has been reported that triphenylphosphine can catalyze the cycloaddition reaction of MBH carbonates of isatins with some activated alkenes to give diverse spirooxindoles [38][39][40][41]. The reaction of

Three-component reactions of conjugated dienes, CH acids and formaldehyde under diffusion mixing conditions

• Dmitry E. Shybanov,
• Maxim E. Kukushkin,
• Eugene V. Babaev,
• Nikolai V. Zyk and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2025, 21, 262–269, doi:10.3762/bjoc.21.18

• main reaction products. Keywords: aldol condensation; [4 + 2]-cycloaddition; diffusion mixing; formaldehyde; Knoevenagel condensation; three-component reactions; Introduction Formaldehyde is a reactive electrophilic reagent widely used as a C1 building block in multicomponent reactions [1][2][3]. Its

• method was successfully used to generate highly active nitrile oxides and nitrilimines for 1,3-dipolar cycloaddition reactions [19][20][21]. Based on our previous experience with diffusion mixing, we assumed that formaldehyde vapor diffusion into the reaction would lead to an extremely low concentration

• various CH acid derivatives and conjugated dienes (cyclopentadiene, 1,3-cyclohexadiene, 2,3-dimethylbutadiene and isoprene), leading to [4 + 2]-cycloaddition adducts (Scheme 1). It should be noted that in previous works describing three-component reactions of carbonyl compounds, conjugated dienes and

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

• behavior or reactivity properties. The ambiguity related to the role of Cu(OTf)2 is particularly relevant for cycloaddition reactions, where it is even more difficult to justify the activation of the copper species as a Lewis acid or metal catalyst [12][13][14]. The reaction mechanism involved can be ionic

• ] cycloaddition reaction with the nitroalkene produces the pyrrolidine XXVII, which then aromatizes by extrusion of HNO2 (Scheme 21) [38]. Substituted pyrrolidines 30 were achieved in an enantioselective form starting from amino acid esters, electron-poor olefins and 4-substituted-2-picolinaldehydes or 4

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

• are of interest and have been recently investigated by Jørgensen and co-workers. The authors employed an enantioselective aminocatalytic cycloaddition between 5H-benzo[a]pyrrolizine-3-carbaldehydes 22 and naphthyl-substituted nitroalkenes, α,β-unsaturated ketoesters, or α,β-unsaturated aldehydes 23

• enantioselectivities (Scheme 13). Axially chiral compounds with an N–N stereogenic axis can be synthesized by an NHC-catalyzed (3 + 3) annulation [33]. The key feature of this transformation is the cycloaddition of α,β-unsaturated azolium intermediates with thioureas. In this way, a range of diversely substituted N–N

• axially chiral pyrroles and indoles 44 are obtained (Scheme 14). Zhu and co-workers developed a method for the atroposelective formation of arenes 48 by an NHC-catalyzed formal (4 + 2) cycloaddition [34]. The triazolium pre-catalyst (R,S)-C11 was the most efficient in providing a range of biaryls in high

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

• . Photochemical reactions require uniform light penetration of the reaction mixture, and flow setups with uniform path lengths would be ideal for such reactions. A self-optimizing continuous-flow reactor was designed by Poscharny et al. [59] for [2 + 2]-cycloaddition reactions promoted by light. The optimization

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

• 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

• )-catalyzed [2 + 2 + 2] cycloaddition reactions with 1,8-dialkynylnaphthalenes to access azafluoranthenes and 2-pyridone-fused naphthalenes [27]. In 2017, we reported a Pd-catalyzed cascade reaction that involves a sequential Suzuki–Miyaura cross-coupling and a subsequent intramolecular C–H arylation between

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

• Sergio Torres-Oya Mercedes Zurro Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación Química “Andrés M. del Río” (IQAR), Universidad de Alcalá (IRYCIS), 28805 Madrid, Spain 10.3762/bjoc.20.268 Abstract Asymmetric cycloaddition is a straightforward strategy which

• , they can be attacked by a nucleophile and undergo a 1,2-addition or conjugate addition leading to the production of allylic amines or aliphatic imines, respectively. They can also behave as C4 synthons in cycloaddition reactions such as the aza-Diels–Alder reaction, giving access to nitrogen-containing

• , respectively. Additionally, the most common cyclic α,β-unsaturated imines involve benzofuran or saccharin-derived azadienes (Figure 1). Cycloaddition reactions, especially Diels–Alder reactions, have attracted a lot of attention since their discovery as one of the most powerful methodologies for the

Germanyl triazoles as a platform for CuAAC diversification and chemoselective orthogonal cross-coupling

• John M. Halford-McGuff,
• Thomas M. Richardson,
• Aidan P. McKay,
• Frederik Peschke,
• Glenn A. Burley and
• Allan J. B. Watson

Beilstein J. Org. Chem. 2024, 20, 3198–3204, doi:10.3762/bjoc.20.265

• 10.3762/bjoc.20.265 Abstract We report the synthesis of germanyl triazoles formed via a copper-catalysed azide–alkyne cycloaddition (CuAAC) of germanyl alkynes. The reaction is often high yielding, functional group tolerant, and compatible with complex molecules. The installation of the Ge moiety enables

• azide precursors and the formation of a single 1,4-disubstituted triazole product, the copper-catalysed azide–alkyne cycloaddition (CuAAC) remains the archetypal click reaction (Scheme 1) [5]. The reaction has shown applicability on small and large scale, as well as under flow conditions [6], and

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

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• cycloaddition, and Ugi reactions followed by Mitsunobu cyclization, among other strategies (Figure 2) [16]. Central nervous system diseases Central nervous system (CNS) diseases are the main cause of disability and the second cause of mortality worldwide, indeed, according to the 2019 World Health Organization

• years, the Ugi reaction has emerged as a highly considered reaction due to its mild conditions, broad applications, and product diversity. It enables the selective assembly of precursors, facilitating various post-reaction transformations such as deprotection cyclization, 1,3-dipolar cycloaddition, 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

• hetero-Diels–Alder reaction of Danishefsky's diene 6 with p-nitrobenzaldehyde (7, Figure 2). The reaction can provide three products depending on the reaction conditions; either a Mukaiyama aldol (8) or products of Diels–Alder cycloaddition (9 and 10). Out of the three screened catalysts, only calix[4

• ]pyrrole α,β-isomer 4 was found to be catalytically active providing a 57% conversion to 10, suggesting a concerted cycloaddition mechanism. Calix[4]pyrrole α,α-isomer 3 and dipyrromethane 5 were catalytically inactive. The authors concluded that the catalytic inactivity of 3 is caused by the parallel

• centrifugation. In the same way as a calix[4]pyrrole was used as organocatalyst for cyclic carbonate synthesis from epoxide and CO2, as discussed in section 1.1, Gallo and co-workers investigated the organocatalytic activity of porphyrin/TBACl binary catalytic systems for the regioselective cycloaddition of CO2

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

• . Photometric monitoring of the irradiation of 1i (A) and 1l (B) in the presence of [Ru(phen)3](PF6)2; λex = 520 nm. For clarity, the absorption of the sensitizer has been deducted. Insets: plot of absorption at long-wavelength maximum versus irradiation time t [38]. Photoinduced [2 + 2]-cycloaddition

Synthesis of fluorinated acid-functionalized, electron-rich nickel porphyrins

• Mike Brockmann,
• Jonas Lobbel,
• Lara Unterriker and
• Rainer Herges

Beilstein J. Org. Chem. 2024, 20, 2954–2958, doi:10.3762/bjoc.20.248

• ]. Beyond their essential biological roles, porphyrins and their derivatives are employed in a number of applications, acting as catalysts in numerous reactions, including oxidation, reduction, and cycloaddition [6][7][8][9][10]. Particularly when electron-rich porphyrins act as reducing agents, e.g. in

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

• with 1,10-phenanthroline as cyclic imine under solvent-free conditions for the synthesis of pyrrole-fused phenanthroline. This reaction proceeds via in situ formation of zwitterion I through reaction of the aldehyde and malononitrile followed by 1,3-dipolar cycloaddition (Scheme 1a) [41]. Chen and co

Synthesis of spiroindolenines through a one-pot multistep process mediated by visible light

• Francesco Gambuti,
• Jacopo Pizzorno,
• Chiara Lambruschini,
• Renata Riva and
• Lisa Moni

Beilstein J. Org. Chem. 2024, 20, 2722–2731, doi:10.3762/bjoc.20.230

• the acid-catalyzed [4 + 1] cycloaddition of commercially available substrates, as indoles and nitroalkenes to give spiro-isoxazoles (Scheme 1c), but acceptable yields were obtained just using nitrostyrenes [13][14]. Despite these examples, the highly efficient construction of structurally diverse