Pentacyclic aromatic heterocycles from Pd-catalyzed annulation of 1,5-diaryl-1,2,3-triazoles

• Kaylen D. Lathrum,
• Emily M. Hanneken,
• Katelyn R. Grzelak and
• James T. Fletcher

Beilstein J. Org. Chem. 2025, 21, 2524–2534, doi:10.3762/bjoc.21.194

• tandem approach preparing 7–12 ranged from 43–85%, which were similar to running the deprotection and cycloaddition reactions sequentially. Pd-catalyzed annulation using a modification of previously reported reaction conditions [46] under microwave irradiation instead of thermal heating converted 1,5

The high potential of methyl laurate as a recyclable competitor to conventional toxic solvents in [3 + 2] cycloaddition reactions

• Ayhan Yıldırım and
• Mustafa Göker

Beilstein J. Org. Chem. 2025, 21, 2389–2415, doi:10.3762/bjoc.21.184

• context of these strategies, it would be judicious to consider cycloaddition reactions of the [3 + 2] type, a field in which Smith and Huisgen are recognized as pioneers [24][25]. In the field of heterocyclic chemistry, the [3 + 2] type of cycloaddition reaction is a widely employed method for the

• consisting of a combination of isoxazolidine rings [36][37][38][39][40][41]. It has been demonstrated that such cycloaddition reactions are also employed in the efficient preparation of biologically active molecules, including nucleosides, β-lactam class antibiotics, peptides, and amino acids, as well as

• sugars (Figure 1) [42][43][44][45][46][47][48]. More specifically cycloaddition reactions of nitrones (1,3-dipoles) with N-aryl-substituted maleimides (electron-poor dipolarophiles) are a highly popular and versatile method for the formation of regio- and stereoselective pyrrolo-isoxazolidine-fused ring

C2 to C6 biobased carbonyl platforms for fine chemistry

• Jingjing Jiang,
• Muhammad Noman Haider Tariq,
• Florence Popowycz,
• Yanlong Gu and
• Yves Queneau

Beilstein J. Org. Chem. 2025, 21, 2103–2172, doi:10.3762/bjoc.21.165

• . Then, through acetylation and subsequent base-mediated oxidopyrylium [5 + 2] cycloaddition reactions, 1-(trifluoromethyl)-8-oxabicyclo[3.2.1]oct-3-en-2-ones were prepared (Scheme 58) [190]. Chu and Webster reported the photocatalyzed synthesis of furfural-derived diacids from furfural [191][192

α-Ketoglutaric acid in Ugi reactions and Ugi/aza-Wittig tandem reactions

• Vladyslav O. Honcharov,
• Yana I. Sakhno,
• Olena H. Shvets,
• Vyacheslav E. Saraev,
• Svitlana V. Shishkina,
• Tetyana V. Shcherbakova and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2025, 21, 2021–2029, doi:10.3762/bjoc.21.157

• for the preparation of benzodiazepinone derivatives, which showed promising psychotropic effects [20][21][22][23][24], using a tandem combination of Ugi/azide–alkyne cycloaddition reactions. From this point of view, azido amines are promising reagents for use in the Ugi reaction, opening up the

Understanding the origin of stereoselectivity in the photochemical denitrogenation of 2,3-diazabicyclo[2.2.1]heptene and its derivatives with non-adiabatic molecular dynamics

• Leticia A. Gomes and
• Steven A. Lopez

Beilstein J. Org. Chem. 2025, 21, 2007–2020, doi:10.3762/bjoc.21.156

• starting materials for different types of reactions including thermal isomerization to cyclopentenes [36][37][38] and 1,4-pentadienes [37][38], chemical electron-transfer oxidations to cyclopentene [39] and cycloaddition reactions with electron-deficient alkenes and alkynes [38][40][41] (Scheme 1b

Preparation of spirocyclic oxindoles by cyclisation of an oxime to a nitrone and dipolar cycloaddition

• Beth L. Ritchie,
• Alexandra Longcake and
• Iain Coldham

Beilstein J. Org. Chem. 2025, 21, 1890–1896, doi:10.3762/bjoc.21.146

• -containing compounds makes use of intramolecular 1,3-dipolar cycloaddition reactions [15], including examples with nitrone ylides [16][17][18][19][20][21][22]. Our research group has exploited this approach for the synthesis of alkaloids such as myrioxazine A and aspidospermidine [23][24]. With a nitrone 1,3

[3 + 2] Cycloaddition of thioformylium methylide with various arylidene-azolones in the synthesis of 7-thia-3-azaspiro[4.4]nonan-4-ones

• Daniil I. Rudik,
• Irina V. Tiushina,
• Anatoly I. Sokolov,
• Alexander Yu. Smirnov,
• Alexander R. Romanenko,
• Alexander A. Korlyukov,
• Andrey A. Mikhaylov and
• Mikhail S. Baranov

Beilstein J. Org. Chem. 2025, 21, 1791–1798, doi:10.3762/bjoc.21.141

• -membered heterocyclic ring are of particular interest, since they exhibit a wide range of pharmacological activity (Scheme 1) [6][7][8][9][10][11]. The most straightforward and powerful methods of such substance’s syntheses are based on cycloaddition reactions [12][13][14][15]. Previously, we and other

Catalytic asymmetric reactions of isocyanides for constructing non-central chirality

• Jia-Yu Liao

Beilstein J. Org. Chem. 2025, 21, 1648–1660, doi:10.3762/bjoc.21.129

• ], insertion reactions [16][17][18], cycloaddition reactions (e.g., [4 + 1], [3 + 2]) [19][20], and others [21][22][23]. Particularly, isocyanides have been widely exploited toward the preparation of centrally chiral structures through transition-metal-catalyzed or organocatalytic asymmetric reactions [24][25

Transition-state aromaticity and its relationship with reactivity in pericyclic reactions

• Israel Fernández

Beilstein J. Org. Chem. 2025, 21, 1613–1626, doi:10.3762/bjoc.21.125

• ”. This initial recognition was later generalized by Zimmerman and Dewar [13][14] who extended the Hückel–Möbius aromaticity concepts to different pericyclic reactions including not only cycloaddition reactions but also electrocyclizations or sigmatropic reactions, linking them to the Woodward–Hoffmann

• accelerate Diels–Alder cycloaddition reactions [30][31]. In addition, these LA-catalyzed cycloadditions not only exhibit higher reaction rates but also become, in many cases, more regio- and stereoselective than the corresponding uncatalyzed reactions. For these reasons, LAs have been (and still are) widely

• computed lower strain energy and ultimately into the lower barrier. 1,3-Dipolar cycloaddition reactions between azides and metal cyaphide complexes Similar to the Diels–Alder cycloaddition reaction, the 1,3-dipolar cycloaddition between a 1,3-dipole (acting as 4π system) and a 2π dipolarophile is a widely

Facile synthesis of hydantoin/1,2,4-oxadiazoline spiro-compounds via 1,3-dipolar cycloaddition of nitrile oxides to 5-iminohydantoins

• Juliana V. Petrova,
• Varvara T. Tkachenko,
• Victor A. Tafeenko,
• Anna S. Pestretsova,
• Vadim S. Pokrovsky,
• Maxim E. Kukushkin and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2025, 21, 1552–1560, doi:10.3762/bjoc.21.118

• Federation, 115478, Moscow, Russian Federation 10.3762/bjoc.21.118 Abstract The cycloaddition of 1,3-dipoles at C=N bonds is a relatively rare process, in contrast to the widespread cycloaddition reactions at C=C, C≡C, and C=S bonds. In this study, we present the syntheses of novel hydantoin/1,2,4

• -CH3 to -OCH3 led to a decrease in IC50 by at least 20 µM and turned out to be comparable to that obtained for 5d. Conclusion In this study, we firstly investigated the 1,3-dipolar cycloaddition reactions of nitrile oxides to 5-iminohydantoins at their exocyclic C=N bond. A convenient preparative

Ambident reactivity of enolizable 5-mercapto-1H-tetrazoles in trapping reactions with in situ-generated thiocarbonyl S-methanides derived from sterically crowded cycloaliphatic thioketones

• Grzegorz Mlostoń,
• Małgorzata Celeda,
• Marcin Palusiak,
• Heinz Heimgartner,
• Marta Denel-Bobrowska and
• Agnieszka B. Olejniczak

Beilstein J. Org. Chem. 2025, 21, 1508–1519, doi:10.3762/bjoc.21.113

• derived from 5-mercapto-1H-tetrazoles was also examined. Keywords: 2,5-dihydro-1,3,4-thiadiazoles; enolizable 5-mercapto-1H-tetrazoles; insertion reactions; thiiranes; thiocarbonyl ylides; X-ray analysis; Introduction Cycloaddition reactions, including 1,3-dipolar cycloadditions, are considered as one

• ]. Thiocarbonyl S-methanides (thiocarbonyl ylides) 1, which were first reported in the 1980s by R. Huisgen and co-workers contributed to a substantial extension of mechanistic interpretations of cycloaddition reactions and to rapid development of methods applied not only for the synthesis of sulfur heterocycles

• five-membered heterocycles via [3 + 2]-cycloaddition reactions. Depending on the type of the dipolarophile used in these reactions, the target heterocycles may contain only one sulfur atom (cycloadditions with C=C or C≡C dipolarophiles) or more heteroatoms (cycloadditions with C=S, C=O, C=N, N=N, S=O

Enhancing chemical synthesis planning: automated quantum mechanics-based regioselectivity prediction for C–H activation with directing groups

• Julius Seumer,
• Nicolai Ree and
• Jan H. Jensen

Beilstein J. Org. Chem. 2025, 21, 1171–1182, doi:10.3762/bjoc.21.94

• atom transfer and cycloaddition reactions have reported correlation coefficients (R2) of around 0.7 at best, indicating significant deviations from ideal behaviour [12][13]. This means that even when intermediate energies are accurately computed, the predicted regioselectivity may still carry a degree

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

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

• process (Figure 2B) [19]. In a bid to translate sensitization reaction probes to meaningful synthetic transformations, conventional intermolecular [2 + 2] cycloaddition reactions were initially trialled (Figure 3A). Preliminary reactions using styrene or methyl acrylate were unsuccessful, with no [2 + 2

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

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

• ] cycloaddition reactions, states that for the reaction to occur, the distance between the centers of the double bonds must be less than 4.2 Å, and the double bonds must be coplanar and parallel [11]. Designing topochemically active compounds is a challenging task, as the crystal packing mode must first be

• compounds capable of undergoing topochemical [2 + 2] cycloaddition reactions initiated by visible light. A number of related bimane structures have been reported. These include anti-(Ph,Cl)bimane (CPDZBO10) where the Ph residues impart a bowl-shaped bimane distortion and syn-(Ph,Cl)bimane [25], anti-(H,Me

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

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

• 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

• under the above conditions to form highly reactive intermediates capable of [4 + 2]-cycloaddition reactions. Cyclopentadiene, cyclohexadiene, 2,3-dimethylbutadiene and isoprene were used as traps for the intermediates formed. The results are presented in Scheme 3. In general, the reactions produced

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

• 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

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

• )-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

• , 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

• Brønsted acid catalysis has been widely studied in asymmetric synthesis [38][39]. While the asymmetric transformations of 2-azadienes have been more intensively investigated, enantioselective derivatizations of 1-azadienes are scarce. In this section, the cycloaddition reactions involving α,β-unsaturated

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

• isocyanides forms the imidoyl radicals, which undergo intramolecular cyclization and oxidative dehydrogenation to give phenanthridines (Scheme 27) [100]. Conclusion In this Perspective, the addition and cycloaddition reactions of heteroatom radicals with isocyanides have been described in detail and their

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178