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

• employed an I2/DMSO-facilitated C–C bond-scission strategy of styrenes, followed by C–N bond formation and subsequent [4 + 2] annulation. Jiang and co-workers developed a method for synthesizing 4-substituted quinolines using vinyl azides as dual synthons, facilitating both the C–C and C–N bond cleavage

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

• 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

• chemistry [91][92][93]. Among the number of dipolarophiles compatible with this [3 + 2]-cycloaddition, phosphaalkynes [94][95][96] and arsaalkynes [97] have been recently used because they allow easy access to novel heterocycles. For instance, when using organic azides as dipoles, the transformation leads

• , very recently it was found that the C≡P moiety, in particular, can be stabilized in the form of a cyaphide ligand bonded to a metal fragment [99][100]. These cyaphide complexes are proven to readily undergo 1,3-dipolar cycloaddition reactions with organic azides [99][100][101], affording novel metal

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

• biomass-derived CyreneTM can be utilized as an alternative reaction medium for the one-pot copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction of various acetylenes and azides. Due to the strong solvating power of CyreneTM, a sequenced one-pot synthesis of triazoles was successfully

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

• potentially reactive functional groups such as alkenes, alkynes, halides or azides. In 2023, Coote et al. developed a synthetic approach to functionalised spirocyclic oxetanes 83 by combining a Paternò–Büchi reaction with succinic anhydride opening and esterification (Scheme 22) [63]. The key intermediates 82

• nucleophiles, thus providing access to oxetane sulphonamides, sulphonyl azides, sulphonates and sulphones [93]. In 2024, Soós et al. published a similarly mild protocol for the synthesis of amide bioisosteres which utilises Katritzky’s benzotriazole chemistry (Scheme 42) [94]. Unlike the Bull’s methodology

Synthesis of β-ketophosphonates through aerobic copper(II)-mediated phosphorylation of enol acetates

• Alexander S. Budnikov,
• Igor B. Krylov,
• Fedor K. Monin,
• Valentina M. Merkulova,
• Alexey I. Ilovaisky,
• Liu Yan,
• Bing Yu and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2025, 21, 1192–1200, doi:10.3762/bjoc.21.96

• oxyphosphorylation of styrenes [40], this strategy was further extended [41] to phenylacetylenes [42][43][44], cinnamic [45][46][47][48] and α,β-alkynyl carboxylic acids [42], and vinyl azides [49][50] (Scheme 1a). As a rule, transition metal catalysts (Fe [42][44][51][52], Cu [42][44][46][51][53], Ag [54], Mn [55

• synthetic step distinguishes them from the less accessible substituted vinylarenes, alkynes, cinnamic and α,β-alkynyl carboxylic acids, as well as vinyl azides. In addition, compared to similar silyl and alkyl enol ethers, enol acetates are more resistant to solvolysis, which prevents unwanted side

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

• N,N-disubstituted acrylamides [30]. Catalyst-tuned regio- and enantioselective C(sp3)–C(sp3) coupling [31]. Catalyst-controlled annulations of bicyclo[1.1.0]butanes with vinyl azides [32]. Solvent-driven reversible macrocycle-to-macrocycle interconversion [39]. Unexpected solvent-dependent

Photocatalyzed elaboration of antibody-based bioconjugates

• Marine Le Stum,
• Eugénie Romero and
• Gary A. Molander

Beilstein J. Org. Chem. 2025, 21, 616–629, doi:10.3762/bjoc.21.49

• particularly useful and important tool in which azides and other dipolar species engage with reactive alkenes and alkynes on non-canonical amino acids [20]. Transition-metal-mediated processes, including metathesis reactions, aryl cross-coupling reactions, and conjugate addition reactions with dehydroalanine

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

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

• other hand, 4-(α-tetrasubstituted)alkyl-1,2,3-triazoles 45 can be obtained by a two-step reaction of cyclohexanone, amines, silylacetylene, and aryl or alkyl azides in the presence of copper(II) catalysts (Scheme 34) [53]. In a first step, there is the formation of a propargylamine derivative XLIII

Reactivity of hypervalent iodine(III) reagents bearing a benzylamine with sulfenate salts

• Beatriz Dedeiras,
• Catarina S. Caldeira,
• José C. Cunha,
• Clara S. B. Gomes and
• M. Manuel B. Marques

Beilstein J. Org. Chem. 2024, 20, 3281–3289, doi:10.3762/bjoc.20.272

• have been reported [12]. These reagents have proven effective in delivering azides (I) [13], amides (II) [14], aliphatic cyclic amines (III) [15], phthalimidates (IV) [16], imines (V) [17], sulfoximides (VI) [18], carbazoles (VII) [19], secondary (VIII) [4] and primary (IX) [20] amines (Figure 1). 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

• clean conversion to the desired triazole products 1–21 without any observable degermylation or other side reactions that could be anticipated based on transmetalation to Cu [43]. The generality of the CuAAC process was explored using a range of azides (Scheme 2a), with variation of the germanyl alkyne

• reactivity compared to other alkynes, which typically require much shorter reaction times. Extending the reaction time provided a higher conversion to the product 14. Yields were observed to be greater for aryl azides (e.g., 4 vs 6). Heterocycles such as pyridine (1), pyrimidine (10), phenothiazine (11), and

• chromene (12) were tolerated. Benzylic azides were accommodated including those bearing nitro (2), iodo (3), and boronic ester groups (5, 21). Strained rings were effective including cubane (18) and bicyclopentane (20). While 18 and 20 were isolated in lower yield, no evidence of ring opening was observed

Synthesis of 2H-azirine-2,2-dicarboxylic acids and their derivatives

• Anastasiya V. Agafonova,
• Mikhail S. Novikov and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2024, 20, 3191–3197, doi:10.3762/bjoc.20.264

• their amides, esters, and azides by FeCl2-catalyzed isomerization of 3-aryl-5-chloroisoxazole-4-carbonyl chlorides into 3-aryl-2H-azirine-2,2-dicarbonyl dichlorides followed by their reaction with nucleophiles are reported. Two approaches to the preparation of 3-aryl-5-chloroisoxazole-4-carbonyl

• -ylcarbonyl)-2H-azirines, 1-(2H-azirine-2-carbonyl)benzotriazoles, 2H-azirine-2-carbonyl azides, anhydrides, amides, esters, and thioesters of azirine carboxylic acids, as well as azirine carboxylic acids themselves, have been prepared over the last decade (see [2] and references therein). Azirine-2

• reaction sequences for the synthesis of 3-aryl-5-chloroisoxazole-4-carbonyl chlorides have been developed. These compounds are convenient precursors for the preparation of 2H-azirine-2,2-dicarboxylic acids and their derivatives such as amides, esters and azides, via an Fe(II)-catalyzed room temperature

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

• ), respectively. Preventive education for synthesizing triazolobenzodiazepine 6a–h Azides are highly reactive, toxic, explosive, and shock-sensitive chemicals that can be used under certain conditions. Special safety procedures must be followed during preparation, storage, handling, and disposal. TMSN3 is an

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

• -catalyzed protocol to obtain spiro[benzo[e][1,3]oxazine-2,3’-indoles] starting from 2-alkynylphenyl azides and 1,2-benzisoxazoles [12] (Scheme 1b). However, all these processes generally involve the preparation of starting materials, often not trivial. On the other hand, in 2018 Aksenov and Rubin reported

Metal-free double azide addition to strained alkynes of an octadehydrodibenzo[12]annulene derivative with electron-withdrawing substituents

• Naoki Takeda,
• Shuichi Akasaka,
• Susumu Kawauchi and
• Tsuyoshi Michinobu

Beilstein J. Org. Chem. 2024, 20, 2234–2241, doi:10.3762/bjoc.20.191

• the field of bioconjugation and materials research. We previously reported a regioselective double addition of organic azides to octadehydrodibenzo[12]annulene derivatives with electron-rich alkyloxy substituents. In order to increase the reaction rate, electron-withdrawing substituents were

• introduced into octadehydrodibenzo[12]annulene. In this report, the synthesis of new octadehydrodibenzo[12]annulene derivatives, regioselective double addition of organic azides, and an application to crosslinking polymers are described. Keywords: annulene; click chemistry; polymerization; strain-promoted

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

• in situ preparation of diazo compounds, as the substances are difficult to handle and toxic [170]. Approaches such as nitrogen transfer with tosylhydrazones, use of the Bestmann–Ohira reagent, or transformation of primary amines or azides, among others, represent viable and practical options. Diazo

• toluene [173]. N-Vinylimidazole, an alkene with a leaving group, was used to synthesize the 3-substituted pyrazoles 169 because, unlike acetylene, it is not gaseous and, therefore, easier to handle. Instead of vinylimidazole, vinyl azides 170 can also be used as alkyne surrogates. After the 1,3-dipolar

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

• comprising a GBB-3CR and a palladium-catalyzed azide-isocyanide coupling to generate imidazo[1,2-a]pyridine-fused 1,3-benzodiazepines 85 (Scheme 27). The GBB reaction smoothly proceeded using 2-azidobenzaldehydes 83, 2-aminopyridines and isocyanides as the precursors. The in situ-generated azides 84 were

Tetrabutylammonium iodide-catalyzed oxidative α-azidation of β-ketocarbonyl compounds using sodium azide

• Christopher Mairhofer,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1510–1517, doi:10.3762/bjoc.20.135

• consequence, the synthesis of organic azides is an important task and it comes as no surprise that a variety of conceptually complementary strategies to install azide groups in organic molecules have been reported [1][2][3][4][5][6][7][8]. α-Azido carbonyl derivatives are especially interesting targets which

• can be accessed by different approaches [6][7][8]. Maybe the most classical way to access organic azides is based on the utilization of pre-functionalized starting materials where a suited leaving group undergoes substitution using nucleophilic azide sources such as NaN3 or TMSN3 [6][7][15]. In

• powerful approaches to access valuable organic azides. In this contribution we report the direct α-azidation of cyclic β-ketocarbonyl compounds using NaN3. This coupling of two inherently nucleophilic species is possible by carrying out the reaction under oxidative conditions using dibenzoyl peroxide in

Synthesis of substituted triazole–pyrazole hybrids using triazenylpyrazole precursors

• Simone Gräßle,
• Laura Holzhauer,
• Nicolai Wippert,
• Olaf Fuhr,
• Martin Nieger,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2024, 20, 1396–1404, doi:10.3762/bjoc.20.121

• the triazole unit via a copper-catalyzed azide–alkyne cycloaddition. The developed methodology was used to synthesize a library of over fifty new multi-substituted pyrazole–triazole hybrids. We also demonstrate a one-pot strategy that renders the isolation of potentially hazardous azides obsolete. In

• cholerae [13], show antimicrobial properties [14], and can act as P2X7 antagonists, a receptor involved in neuroinflammation and depression [15]. Pyrazolyltriazoles are most easily obtained via the copper-catalyzed azide–alkyne cycloaddition (CuAAC) from pyrazolyl azides (7 and 8). These are usually

• predominant product (see 18i and 18j). In total, 13 groups could be attached to the different triazenylpyrazoles, yielding 18 products (see Table 1). In analogy to reported procedures for cleavage of polymer-bound triazenes [23], we attempted to develop the first protocol for synthesizing pyrazolyl azides 19

Innovative synthesis of drug-like molecules using tetrazole as core building blocks

• Jingyao Li,
• Ajay L. Chandgude,
• Qiang Zheng and
• Alexander Dömling

Beilstein J. Org. Chem. 2024, 20, 950–958, doi:10.3762/bjoc.20.85

• . Trimethylsilyl azide is considered as a safe replacement of metal azides. We started the solvent optimization with MeOH and H2O as solvent system at room temperature, however, it did not yield any product even after 3 days (Table 1, entry 1). The use of DMF to improve the solubility of the paraformaldehyde solid

SOMOphilic alkyne vs radical-polar crossover approaches: The full story of the azido-alkynylation of alkenes

• Julien Borrel and
• Jerome Waser

Beilstein J. Org. Chem. 2024, 20, 701–713, doi:10.3762/bjoc.20.64

• discovery and development of the synthesis of homopropargylic azides by the azido-alkynylation of alkenes. Initially, a strategy involving SOMOphilic alkynes was adopted, but only resulted in a 29% yield of the desired product. By switching to a radical-polar crossover approach and after optimization, a

• high yield (72%) of the homopropargylic azide was reached. Full insights are given about the factors that were essential for the success of the optimization process. Keywords: alkyne; azide; hypervalent iodine; photoredox; trifluoroborate salt; Introduction Homopropargylic azides are important

• terminal azide, despite its implication in the synthesis of complex molecules [3][6]. Therefore, the development of a straightforward reaction to synthesize homopropargylic azides would be of general interest. The azido-alkynylation of alkenes would allow to generate the desired motif in a single step

Unveiling the regioselectivity of rhodium(I)-catalyzed [2 + 2 + 2] cycloaddition reactions for open-cage C₇₀ production

• Cristina Castanyer,
• Anna Pla-Quintana,
• Anna Roglans,
• Albert Artigas and
• Miquel Solà

Beilstein J. Org. Chem. 2024, 20, 272–279, doi:10.3762/bjoc.20.28

• cages. However, in other cases, some of the bonds between the C atoms of the cage are broken and the cage is opened. The first example of an open-cage fullerene was reported in 1995 by Hummelen, Prato, and Wudl [21] through the reaction of C60 with azides followed by photooxygenation. Since then, many

Cycloaddition reactions of heterocyclic azides with 2-cyanoacetamidines as a new route to C,N-diheteroarylcarbamidines

• Pavel S. Silaichev,
• Tetyana V. Beryozkina,
• Vsevolod V. Melekhin,
• Valeriy O. Filimonov,
• Andrey N. Maslivets,
• Vladimir G. Ilkin,
• Wim Dehaen and
• Vasiliy A. Bakulev

Beilstein J. Org. Chem. 2024, 20, 17–24, doi:10.3762/bjoc.20.3

• heterocyclic azides followed by a Cornforth-type rearrangement to the final products. The reaction is tolerant to various N-monosubstituted 3,3-diaminoacrylonitriles and to different heterocyclic azides. The developed method has a broad scope and can be applied to obtain a variety of N-heteroaryl-1,2,3

• -triazole-4-carbimidamides with alkyl, allyl, propargyl, benzyl, cycloalkyl, and indolyl substituents at the N1 position . Keywords: Cornforth rearrangement; cycloaddition reactions; 3,3-diaminoacrylonitriles; heterocyclic azides; 1,2,3-triazole; Introduction Heteroaryl amidines are widely used in the

• -diaminoacrylonitriles 1 with heteroaryl azides (HetN3) 2 [16] leading to 5-amino-1,2,3-triazole-4-N-heteroarylcarbimidamides 3 (Scheme 1C). Results and Discussion Optimization of the reaction of amidine 1a with azide 2a We initiated the study by investigating a model reaction involving the cycloaddition of 3-amino-3

Morpholine-mediated defluorinative cycloaddition of gem-difluoroalkenes and organic azides

• Tzu-Yu Huang,
• Mario Djugovski,
• Sweta Adhikari,
• Destinee L. Manning and
• Sudeshna Roy

Beilstein J. Org. Chem. 2023, 19, 1545–1554, doi:10.3762/bjoc.19.111

• gem-difluoroalkenes with organic azides in morpholine as a solvent to construct fully decorated morpholine-substituted 1,2,3-triazoles. Mechanistic studies revealed the formation of an addition–elimination intermediate of morpholine and gem-difluoroalkenes prior to the triazolization reaction via two

• ; gem-difluoroalkenes; organic azides; Introduction gem-Difluoroalkenes and their synthetic preparations soared in the last decade, driven by the high demand for carbonyl mimics in medicinal chemistry and drug discovery [1]. Although a wide array of functionalization strategies for gem-difluoroalkenes

• reactions with azoles and amines (Figure 1B) are also well-precedented [10]. Herein, we address a critical gap in the literature and report the discovery of a cycloaddition of gem-difluoroalkenes and organic azides mediated by a base and with morpholine as a solvent. The cycloaddition adducts, 1,4,5

N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

• Fatemeh Doraghi,
• Seyedeh Pegah Aledavoud,
• Mehdi Ghanbarlou,
• Bagher Larijani and
• Mohammad Mahdavi

Beilstein J. Org. Chem. 2023, 19, 1471–1502, doi:10.3762/bjoc.19.106

• -workers demonstrated bisulfenylation/cyclization of homopropargylic azides 82 with N-thiosuccinimides 1 in the presence of AlCl3 as the catalyst, 3,4-bisthiolated pyrroles 83 were obtained as the desired products in moderate to high yields (Scheme 34) [66]. The reaction involves the Lewis acid-catalyzed

• first thiolation and intramolecular cyclization of propargyl azides the removal of N2 and a proton. Subsequently, monothiolated perroles were subjected to the second thiolation process to prepare 3,4-bisthiolated pyrroles. Cyclic voltammetry and DFT calculations revealed that the 3,4-bisthiolated