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

• an important class of compounds with significant biological activities. Spirocyclic derivatives are present in a variety of natural products. We describe here the formation of spirooxindoles using an intermolecular nitrone cycloaddition reaction. The nitrone dipole was prepared in situ by cyclisation

• condensation, cyclisation, and cycloaddition as an efficient strategy for the rapid formation of complex spirocyclic products that could have value for the formation of novel, bioactive oxindoles. Keywords: cascade; cycloaddition; oxindole; spirocycle; stereochemistry; Introduction The Alstonia alkaloids are

• -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

Chiral phosphoric acid-catalyzed asymmetric synthesis of helically chiral, planarly chiral and inherently chiral molecules

• Wei Liu and
• Xiaoyu Yang

Beilstein J. Org. Chem. 2025, 21, 1864–1889, doi:10.3762/bjoc.21.145

• , including the asymmetric [2 + 2 + 2] cycloaddition of aryl-substituted polyynes and hydroarylation of alkynes [18][19]. In contrast, the application of asymmetric organocatalysis for enantioselective synthesis of chiral helicenes remains relatively underdeveloped compared to transition metal-catalyzed

• eliminative aromatization sequence [23]. The CPA-catalyzed asymmetric [3 + 2]-cycloaddition of cycloenecarbamates 21 and carbalkoxy-substituted azonaphthalenes 22 produced the hexacyclic products 23' with two contiguous stereogenic centers, which then underwent an eliminative aromatization process to yield

• through a [3 + 3]-cycloaddition reaction. By employing the CPA-catalyzed asymmetric electrophilic amination reaction with azodicarboxylate on the phenol moiety, efficient kinetic resolution of 25 proceeded to yield both the amination products 26 and the recovered starting material with high

Fe-catalyzed efficient synthesis of 2,4- and 4-substituted quinolines via C(sp²)–C(sp²) bond scission of styrenes

• Prafull A. Jagtap,
• Manish M. Petkar,
• Vaishnavi R. Sawant and
• Bhalchandra M. Bhanage

Beilstein J. Org. Chem. 2025, 21, 1799–1807, doi:10.3762/bjoc.21.142

• cycloaddition, tandem annulation, intramolecular cyclization, and cross-coupling reactions are commonly employed under thermal conditions, utilizing metal catalysts based on Pd, Ru, Au, Cu, and Fe to access a wide array of substituted quinoline frameworks [29][30][31][32][33][34][35][36][37][38]. Conversely, in

• the FeIII species. An alternative mechanism involving a concerted [4 + 2] cycloaddition between the aza-butadiene moiety in II and the alkene, leading to intermediate IV, cannot be ruled out. Conclusion In summary, we have successfully developed a highly efficient method for the oxidative C–C bond

[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

• single either cis or trans stereoisomers, dependent on the heterocycle core used. Keywords: arylidene-azolones; cycloaddition; nitrogen heterocycles; sulfur heterocycles; thioformylium methylide; Introduction Spirocyclic derivatives of heterocycles occupy an important place in modern organic and

• -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

• tetrahydrothiophenes are known to exhibit different biological activities [8]. However, to date the use of this reagent in the synthesis of spirocyclic derivatives to our knowledge is underinvestigated [26][27]. Results and Discussion In this work we present a systematic study of [3 + 2] cycloaddition of thioformylium

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

• thionolactones, getting rid of the pre-formation of stoichiometric Ru-complexes [52][53]. Mechanistic investigations indicated that this transformation proceeds through a two-step sequence promoted by the same catalyst: 1) the diastereo- and enantioselective [3 + 2] cycloaddition to generate spiro-S,O-ketal 52

• issues of diastereo- and enantioselectivity are required to be addressed appropriately to prevent forming a complex mixture of stereoisomers. In 2022, our group developed a silver-catalyzed desymmetric [3 + 2] cycloaddition between prochiral N-aryl maleimides 57 and α-substituted α-acidic isocyanides

Photocatalysis and photochemistry in organic synthesis

• Timothy Noël and
• Bartholomäus Pieber

Beilstein J. Org. Chem. 2025, 21, 1645–1647, doi:10.3762/bjoc.21.128

• ], hydrogen atom transfer [22], halogen atom transfer [23], and energy transfer catalysis [24][25] – have been established as powerful additions to the arsenal of photon-driven reactions. Three articles in this thematic issue exemplify this: The Molloy group developed an intramolecular [2 + 2]-cycloaddition

Formal synthesis of a selective estrogen receptor modulator with tetrahydrofluorenone structure using [3 + 2 + 1] cycloaddition of yne-vinylcyclopropanes and CO

• Jing Zhang,
• Guanyu Zhang,
• Hongxi Bai and
• Zhi-Xiang Yu

Beilstein J. Org. Chem. 2025, 21, 1639–1644, doi:10.3762/bjoc.21.127

• the 6/5/5 skeleton, and a Heck coupling reaction constructing the [3.2.1] framework, are the two key reactions in this 11-step synthesis. Keywords: [3 + 2 + 1] cycloaddition; selective estrogen receptor modulators; synthesis; tetrahydrofluorenone; Introduction Estrogen receptors (ERs) [1][2] are

• asymmetric Lu [3 + 2] cycloaddition reaction [20][21] between indanone and allenyl ketone. Then hydrogenation and Robinson annulation delivered the core of the target molecule. Some other excellent synthetic routes for tetrahydrofluorenone derivates have been developed [12][13][14][15][16][17][18][19] but

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

• transition structure of the Diels–Alder cycloaddition reaction between butadiene and ethylene “…Very qualitatively, we may say that whereas in the initial state the mobile electrons are those characteristics of an ethylene and a butadiene structure, in the TS they simulate the behavior of a benzene molecule

• ”. 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

3-Aryl-2H-azirines as annulation reagents in the Ni(II)-catalyzed synthesis of 1H-benzo[4,5]thieno[3,2-b]pyrroles

• Julia I. Pavlenko,
• Pavel A. Sakharov,
• Anastasiya V. Agafonova,
• Derenik A. Isadzhanyan,
• Alexander F. Khlebnikov and
• Mikhail S. Novikov

Beilstein J. Org. Chem. 2025, 21, 1595–1602, doi:10.3762/bjoc.21.123

• arenes with azirines. These include the [3 + 2] cycloaddition of azirines to arynes (Scheme 1, reaction 1) [10][11][12], Pd-catalyzed reaction of azirines with iodoarenes (Scheme 1, reaction 2) [13], and reaction of 2-aroylazirines with naphthols (Scheme 1, reaction 3) [8]. The [3 + 2] annulation

• to the azirine C=N bond, followed by cyclization and the aziridine ring opening into the [3 + 2] cycloaddition product 5 (Scheme 3). It is noteworthy that the annulation proceeds via the azirine N‒C3 bond cleavage. Elimination of the methoxycarbonyl group most likely occurs under the action of

• intermediate formation of free radical species [9]. A similar reaction of N-acetyl substituted indole 9c produced [3 + 2] cycloaddition products 12 in even lower yield (4%). However, the main reaction product turned out to be unstable compound 13, which, nevertheless, was isolated in 40% yield as a single

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

• -oxadiazoline spiro-compounds using a 1,3-dipolar cycloaddition of nitrile oxides to C=N bonds of 5-iminohydantoins. The efficiency of the approach was demonstrated by varying the substituents at four positions of the resulting spirocyclic molecules. Cytotoxicity of the target hydantoin/1,2,4-oxadiazolines was

• shown to exceed previously known spiro-compounds bearing only hydantoins or 1,2,4-oxadiazolines (IC50 values were 30–50 μM, HCT116 cell lines). Keywords: 1,3-dipolar cycloaddition; hydantoins; nitrile oxides; Shiff bases; spiro-compounds; Introduction The 1,2,4-oxadiazole fragment is a common

Azide–alkyne cycloaddition (click) reaction in biomass-derived solvent Cyrene^TM under one-pot conditions

• Zoltán Medgyesi and
• László T. Mika

Beilstein J. Org. Chem. 2025, 21, 1544–1551, doi:10.3762/bjoc.21.117

• CyreneTM, as a biomass-originated polar aprotic solvent, could be utilized as an alternative reaction medium for one-pot copper(I)-catalyzed azide–alkyne cycloaddition (click or CuAAC) reactions, for the synthesis of various 1,2,3-triazoles under mild conditions. Nineteen products involving N-substituted-4

• important transformation exhibiting higher chemical and environmental safety. Keywords: alternative solvent; click chemistry; cycloaddition; CyreneTM; 1,2,3-triazoles; Introduction In the past few decades, transition-metal-catalyzed coupling and addition reactions have represented one of the most powerful

• methods, the copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction, the so-called click reaction [7], has received substantial attention for the selective synthesis of various 1,2,3-triazoles that are of utmost importance in the synthesis of biologically active compounds such as active

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

• ]-cycloaddition of respective thiocarbonyl dipolarophiles (preferably non-enolizable thioketones) with diazomethane, was demonstrated as a favorable method for their generation [5][6]. In the past three decades, 1,3-dipoles 1 have extensively been studied as useful building blocks for the preparation of various

Copper catalysis: a constantly evolving field

• Elena Fernández and
• Jaesook Yun

Beilstein J. Org. Chem. 2025, 21, 1477–1479, doi:10.3762/bjoc.21.109

• , Burley, Watson, and co-workers present a new synthesis of germyl triazoles from germyl alkynes through a copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction [6]. The resulting Ge-substituted triazoles could be further diversified. For example, through chemoselective transition-metal-catalyzed

Advances in nitrogen-containing helicenes: synthesis, chiroptical properties, and optoelectronic applications

• Meng Qiu,
• Jing Du,
• Nai-Te Yao,
• Xin-Yue Wang and
• Han-Yuan Gong

Beilstein J. Org. Chem. 2025, 21, 1422–1453, doi:10.3762/bjoc.21.106

• responses. Concurrently, Tanaka’s group achieved the enantioselective synthesis of aza[6]- and aza[7]helicene-like molecules via Rh(I)/chiral bisphosphine-catalyzed [2 + 2 + 2] cycloaddition [80]. The resulting S-shaped double aza[6]helicene-like compound 66 displayed high enantiomeric excess (up to 89% ee

Oxetanes: formation, reactivity and total syntheses of natural products

• Peter Gabko,
• Martin Kalník and
• Maroš Bella

Beilstein J. Org. Chem. 2025, 21, 1324–1373, doi:10.3762/bjoc.21.101

• ] Cycloadditions Another widely used method for oxetane synthesis is the [2 + 2] cycloaddition between carbonyls and olefins (Scheme 19), and the two main variations include light-induced Paternò–Büchi reactions and Lewis acid- or base-catalysed formal [2 + 2] cycloadditions. The main advantages of these reactions

• extended enolate 96 to the ketone, cyclisation via addition/elimination and base-catalysed epimerisation towards the thermodynamically more stable diastereomer. In 2019, Nair and co-workers showed that this formal cycloaddition can also be performed with 1,2-dicarbonyls as electrophiles and under an

• . published a light-induced cross-selective [2 + 2] cycloaddition between 3-(arylmethylidene)oxetanes 159 and electron-deficient alkenes 160 (Scheme 40) [91]. The methodology used a commercially available iridium-based photosensitiser and blue-light irradiation at a slightly elevated temperature. The

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

A multicomponent reaction-initiated synthesis of imidazopyridine-fused isoquinolinones

• Ashutosh Nath,
• John Mark Awad and
• Wei Zhang

Beilstein J. Org. Chem. 2025, 21, 1161–1169, doi:10.3762/bjoc.21.92

• reaction followed by the cleavage of the alkyl group to give intermediate II as a free amine. Annulation of II with CDI gave product B which is an HIV reverse transcriptase inhibitor (Scheme 1B) [17]. We have reported a three-component [3 + 2] cycloaddition followed by IMDA reaction for making heterocyclic

• charge and the electronic consequences of the 5-Br substitution 6j were considered, which were found to inhibit the system from attaining the requisite conditions for successful cycloaddition. Secondly, the interatomic distances between the reactive centers of the diene and dienophile are almost similar

• for all substitutes of 6a, 6h, 6r and 6j, which, are not ideal effective for IMDA cycloadditions compared to the other substitute cycloadditions. The R2 substituent on the imidazopyridine moiety in 6 was found to have a significant electronic impact on the IMDA cycloaddition. When R2 is a halogen (Br

Salen–scandium(III) complex-catalyzed asymmetric (3 + 2) annulation of aziridines and aldehydes

• Linqiang Wang and
• Jiaxi Xu

Beilstein J. Org. Chem. 2025, 21, 1087–1094, doi:10.3762/bjoc.21.86

• alcohols and aldehydes [11] and through [2 + 3] cycloaddition of azomethine ylides and carbonyl dipolarophiles [12]. Recently, the [2 + 3] annulation of aldehydes and donor–acceptor dialkyl 2-aryl-1-sulfonylaziridine-2,2-dicarboxylates, which generate azomethine ylides, has been developed for the synthesis

• carboxylate groups followed by a ring opening of the aziridine ring, forming azomethine ylide intermediates A. The intermediates A further undergo a [2 + 3] annulation (or cycloaddition) with aldehydes 2 through endo transition state TS to generate intermediates B, which release products 3 with regeneration

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

• scaled up to a gram scale operation. Similarly, Liu and co-workers (2020) reported a Ag2O-catalyzed ring-opening of cylopropenone 309 with oximes to give the corresponding series of novel 1,3-oxazinones 330–332 in good yields. The reaction involves a [4 + 2] cycloaddition (334) of the fragmented

• 350–352 in good yields via benzyne intermediate 353 followed by a [2 + 2] cycloaddition with the sulfoxide affording an o-quinone intermediate 354 (Scheme 78) [132]. Furthermore, dioxolane compounds have also been subjected to synthesize cinnamic acid derivatives through CO2 release. For example, Chen

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

• elegant [2 + 3] cycloaddition of secondary enecarbamates [28], the extension of this reaction to enamides lacking an N–H group is a notable advancement. After extensive optimization, the chiral dirhodium catalyst cat. 1 was found to be most capable in terms of both stereocontrol and efficiency. The use of

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