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

• chloroform, for the [3 + 2] cycloaddition reactions between nitrones and diverse dipolarophiles has not been predicated on any criteria other than their inertness [60]. Conversely, certain studies have reported that the effects of organic solvents in such reactions are negligible, and that an increase in

• ADMETLab 3.0 platform [87] are illustrated in Figure 2a. Conversely, the oral toxicity values of methyl laurate, in conjunction with toluene and chloroform – two conventional solvents that are commonly employed in [3 + 2] cycloaddition reactions were calculated with ProTox 3.0 (a webserver for the

Enantioselective radical chemistry: a bright future ahead

• Anna C. Renner,
• Sagar S. Thorat,
• Hariharaputhiran Subramanian and
• Mukund P. Sibi

Beilstein J. Org. Chem. 2025, 21, 2283–2296, doi:10.3762/bjoc.21.174

• transformations [43][44][45][46][47][48]. Using SOMO catalysis, MacMillan and co-workers developed a method for the synthesis of substituted pyrrolidines from β-aminoaldehydes and olefins in a formal [3 + 2] cycloaddition (Scheme 2) [44]. The transformation was proposed to proceed via a radical–polar crossover

• and pyrrolidinone electrophiles. Organocatalyzed formal [3 + 2] cycloadditions affording substituted pyrrolidines. Synthesis of a hexacyclic compound via an organocatalyzed enantioselective polyene cyclization. Nickel-catalyzed asymmetric cross-coupling reactions. Chiral cobalt–porphyrin

Electrochemical cyclization of alkynes to construct five-membered nitrogen-heterocyclic rings

• Lifen Peng,
• Ting Wang,
• Zhiwen Yuan,
• Bin Li,
• Zilong Tang,
• Xirong Liu,
• Hui Li,
• Guofang Jiang,
• Chunling Zeng,
• Henry N. C. Wong and
• Xiao-Shui Peng

Beilstein J. Org. Chem. 2025, 21, 2173–2201, doi:10.3762/bjoc.21.166

• alkynes, amines and azides, respectively. Imidazopyridines could be obtained by electrochemical [3 + 2] cyclization of heteroarylamines. The electrochemical oxidative [3 + 2] cycloaddition of secondary propargyl alcohols was a simple and efficient access towards 1,2,3-triazoles. In this review

• [61], [3 + 2] reductive cycloadditions of enal-alkyne [62], [2 + 2 + 1] cycloaddition of acetylenes [63] and cyclization of 1,6-enyne [64] were efficient approaches towards five-membered rings. Since Faraday synthesized hydrocarbons by employing electric current to an acetate solution [65], the use of

• reaction avoided the use of metal catalysts and oxidants, but the yields remained to improve. An electrochemical [3 + 2] cyclization of heteroarylamine to access imidazopyridine was achieved by Xu in 2017 (Scheme 18) [270]. When RVC was used as anode, platinum as cathode and Et4NBF4 as electrolyte, the

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

• -synthesis of formamides and formates was achieved in particularly good yield by selective oxidation of DHA using a Cu/Al2O3 catalyst with single active CuII species at room temperature without using a base (Scheme 20). 1-Hydroxypropan-2-one Gu et al. reported the [3 + 2] cyclization reaction of 1

• Meerwein–Ponndorf–Verley reduction, while acetaldehyde is generated in situ by ethanol oxidation (Scheme 50). The equilibrium allows furfural to be simultaneously converted into furfuryl alcohol and 3-(2-furyl)acrolein in one pot through a redox reaction. The highest mass conversion rate of furfural can

• ]. Furfural first was reacted with malonic acid to produce trans-3-(2-furyl)acrylic acid in a Knoevenagel reaction, which was then converted into cyclobutane-containing diacids through a [2 + 2] photoreaction. cis-3,4-Di(furan-2-yl)cyclobutane-1,2-dicarboxylic acid (CBDA-2) prepared under blacklight UV

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

• our simulations. Our predicted inverted-to-retained housane ratios – 4, 7, and 5 for 1, 3, and 5, respectively – are higher than the experimental ratios of 3, 2, and 3. We attribute this overestimation to the limited simulation time of 1 ps. Since retained housane forms via thermal conversion from

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

• 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

[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

• 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

• methylide with various arylidene-azolones. First, a series of various arylidene-azolones 1–5 were prepared (Scheme 2). All compounds were created in accordance with our previously published protocols [20][28][29]. Next, optimization of [3 + 2]-cycloaddition reaction condition was performed using derivatives

• be determined. Conclusion A study on [3 + 2]-cycloaddition reaction of various arylidene-azolones, with thioformylium methylide was performed. We have shown that cesium fluoride or TBAF can be an effective source of fluoride iones for activation of chloromethyl(trimethylsilyl)methyl sulfide. The

Unique halogen–π association detected in single crystals of C–N atropisomeric N-(2-halophenyl)quinolin-2-one derivatives and the thione analogue

• Mai Uchibori,
• Nanami Murate,
• Kanako Shima,
• Tatsunori Sakagami,
• Ko Kanehisa,
• Gary James Richards,
• Akiko Hori and
• Osamu Kitagawa

Beilstein J. Org. Chem. 2025, 21, 1748–1756, doi:10.3762/bjoc.21.138

• chemistry but also medicinal chemistry [10][11][12][13]. For example, 3-(2-bromophenyl)-2-methylquinazolin-4-one (I), which has a high rotational barrier about the N3–Ar bond, is known as mebroqualone possessing GABA agonist activity (Figure 1) [14][15]. Our group has been exploring asymmetric synthesis of

• were formed through an n–π* interaction between a lone electron pair on the halogen atom and a π*orbital of the quinolinone ring. Thus, chirality (racemic/optically pure)-dependent halogen bonding was observed in single crystals of not only 3-(2-halophenyl)quinazolin-4-one derivatives but also N-(2

Convenient alternative synthesis of the Malassezia-derived virulence factor malassezione and related compounds

• Karu Ramesh and
• Stephen L. Bearne

Beilstein J. Org. Chem. 2025, 21, 1730–1736, doi:10.3762/bjoc.21.135

• are uncorrected. tert-Butyl 3-(2-methoxy-2-oxoethyl)-1H-indole-1-carboxylate (21). A solution of indol-3-yl acetic acid (20, 5.1 g, 29.0 mmol, 1.0 equiv) in dry MeOH (200 mL) was cooled to 0 °C, and SOCl2 (10.5 mL, 145 mmol, 5.0 equiv) was added slowly. After stirring for 12 h at room temperature, the

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

• ring were proven to be suitable substrates to react with tert-butyl isocyanoacetate, affording 3-heteroarylpyrroles 41 in 55–99% yield with 70–96% ee. In these cases, additional 2.0 equivalents of DBU were required to facilitate the conversion from the [3 + 2] cycloadducts to the final products

• 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

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

• University, Beijing, 100871, China 10.3762/bjoc.21.127 Abstract A formal synthesis of product VI with tetrahydroflurenone structure as selective estrogen receptor modulator has been realized. The Rh-catalyzed [3 + 2 + 1] reaction of yne-vinylcyclopropanes and CO (20 mmol scale, in 87% yield) for building

• 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

• 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

• comparable to that computed for the non-metallic process (ΔG≠ ≈ 26 kcal/mol). Once again, we explored the impact of the aromaticity of the involved transition structures on the computed barriers. As related [3 + 2] cycloaddition reactions [22][45][104][105], the transition states associated with these

• computed for the 1,3-dipolar cycloadditions involving Mg and Ge cyaphide complexes, the ASM of reactivity was applied. Figure 10a shows the ASDs for the [3 + 2]-cycloaddition reactions between t-BuN3 and [Au]C≡P and [Mg]C≡P cyaphide complexes, as representative systems, from the initial stages of the

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

• , we firstly report the synthesis of compounds comprising two pharmacophoric fragments, hydantoin and 1,2,4-oxadiazoline, joined through the C5 atom of each cycle forming spiro-fused structures. We propose an efficient method for the synthesis of such spiro-compounds based on a [3 + 2]-dipolar

• of double and triple bonds, most of the described reactions are related to dipolarophiles with C=C, C≡C or C=S bonds [7]. However, the [3 + 2]-cycloaddition of nitrile oxides to exocyclic C=N bonds, is a much less explored area. There are few known reactions of these dipoles with imino derivatives of

Azobenzene protonation as a tool for temperature sensing

• Antti Siiskonen,
• Sami Vesamäki and
• Arri Priimagi

Beilstein J. Org. Chem. 2025, 21, 1528–1534, doi:10.3762/bjoc.21.115

• propensity (∆G° = −5.81, −5.25, and −2.55 kcal/mol for 3, 2, and 1, respectively). The protonation is more favorable in DCE (∆G° between −2.55 and −5.81 kcal/mol) than in MeCN (∆G° between −1.74 and −4.74 kcal/mol), highlighting solvent effects on reactivity. For 3 in DCE, the addition of a second MSA

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

• but also for the synthesis of sulfur-containing organic compounds in general [2][5][6]. Thiocarbonyl S-methanides 1 belong to the class of so-called S-centered, electron-rich 1,3-dipoles and in numerous studies, thermal decomposition of 1,3,4-thiadiazolines 2, which are easily accessible via [3 + 2

• 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

• , N=S=O, etc. dipolarophiles) [5][6][7][8][9][10] (Scheme 1, upper part). Notably, [3 + 2]-cycloadditions of the sterically crowded thiocarbonyl S-methanide 1b with electron deficient, tetrasubstituted ethylenes activated with CN and CF3 (or CN and CO2Me) groups were encountered as the first examples

Microwave-enhanced additive-free C–H amination of benzoxazoles catalysed by supported copper

• Andrei Paraschiv,
• Valentina Maruzzo,
• Filippo Pettazzi,
• Stefano Magliocco,
• Paolo Inaudi,
• Daria Brambilla,
• Gloria Berlier,
• Giancarlo Cravotto and
• Katia Martina

Beilstein J. Org. Chem. 2025, 21, 1462–1476, doi:10.3762/bjoc.21.108

• employed to efficiently graft either 3-aminopropyltriethoxysilane (MonoAm) or 3-(2-aminoethylamino)propyltrimethoxysilane (DiAm) (Scheme 2) [51], and the efficiency of derivatisation was measured by thermogravimetric analysis (TGA) as showed in Figure 3. TGA curves were all normalised to 150 °C to

Wittig reaction of cyclobisbiphenylenecarbonyl

• Taito Moribe,
• Junichiro Hirano,
• Hideaki Takano,
• Hiroshi Shinokubo and
• Norihito Fukui

Beilstein J. Org. Chem. 2025, 21, 1454–1461, doi:10.3762/bjoc.21.107

• . A tentative mechanism that may be plausible is shown in Supporting Information File 1, Figure S21, which consists of (1) the nucleophilic attack of methylenetriphenylphosphorane to the exo-methylene group of 3, (2) the intramolecular carbon–carbon-bond formation at the carbonyl group, and (3) the

• slightly preferred at room temperature with approximately a 3:2 ratio of figure-eight and bathtub conformations. We have also estimated the activation barriers of the interconversion of 3 and 5 between the figure-eight and bathtub conformations by measuring VT 1H NMR spectra in toluene-d8 because the

• and rac-5 was conducted using high-performance liquid chromatography (HPLC) equipped with DAICEL CHIRALPAK IE as the chiral stationary phase (eluent: CH2Cl2/hexane 3:2 for 3 and 1:9 for 5). The absolute configurations of the enantiomers were determined by transformation of enantiomerically pure CBBC

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

• 6 exhibiting enhanced chiroptical performance and protonation-induced CPL amplification [19]. Meanwhile, Audisio’s team developed heterohelicenes via regioselective [3 + 2]-cycloadditions, with compound 7 displaying pH-responsive CPL sign inversion (|glum| = +1.1 × 10−3 at 430 nm, −1.2 × 10−3 at 585

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

• -, particularly 2-methylideneoxetanes have become valuable intermediates in oxetane chemistry as they readily undergo a variety of chemical transformations, including ring-opening reactions with nucleophiles, epoxidations, cyclopropanations and [3 + 2] cycloadditions with nitrile oxides [51][52]. In addition

• regioselectivity of the Friedel–Crafts alkylation to the para-position, forming exclusively (or significant amounts of) 3,3-diaryloxetanes. In 2017, Vanderwal and co-workers published a novel, facile synthesis of furans 181 and pyrroles 185 from 3-(2-oxoalkylidene)oxetanes 179, precursors which are readily

• -catalysed heterocycle synthesis, specifically a [3 + 2] annulation of 3-(4-hydroxyphenyl)oxetan-3-ol (211) with β-naphthylamines or phenols 210 to give benzoindolines and 2,3-dihydrobenzofurans 212, respectively (Scheme 50) [104]. The reaction gave moderate to high yields and control experiments indicated

Recent advances and future challenges in the bottom-up synthesis of azulene-embedded nanographenes

• Bartłomiej Pigulski

Beilstein J. Org. Chem. 2025, 21, 1272–1305, doi:10.3762/bjoc.21.99

• CHCl3, AcOH and o-DCB [44]. The resulting mixture of brominated PAHs 30 and 31 was then subjected to single or double [3 + 2] annulation with various alkynes, leading to the extended structures 32 and 33. Notably, compound 33d can undergo Pd-catalysed dimerization, resulting in the formation of a chiral

• characteristics to most azulene-embedded PAHs obtained via Scholl oxidation – specifically, the azulene subunit does not exhibit aromaticity, and the surrounding benzenoid rings predominantly determine the electronic structure of 49. [3 + 2] Annulation of alkynes accompanied by a phenyl ring expansion: The

• and co-workers [55]. A palladium-catalysed variation of [3 + 2] annulation, accompanied by ring expansion [56], was used for the intermolecular reaction between acenes bearing alkyne substituents 55a–d and di-n-butylacetylene (56). The reaction gave a series of azulene-embedded isomers of linear

Recent advances in oxidative radical difunctionalization of N-arylacrylamides enabled by carbon radical reagents

• Jiangfei Chen,
• Yi-Lin Qu,
• Ming Yuan,
• Xiang-Mei Wu,
• Heng-Pei Jiang,
• Ying Fu and
• Shengrong Guo

Beilstein J. Org. Chem. 2025, 21, 1207–1271, doi:10.3762/bjoc.21.98

• -methylpiperidine, proved compatible with the reaction conditions, yielding the corresponding 3-(2-oxoethyl)indolin-2-ones 5a–g in 40–78% yields. Following a detailed investigation, a plausible mechanism was proposed, as illustrated in Scheme 3. Initially, TBHP undergoes cleavage by Fe2+ to generate a tert-butoxy

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

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

• moieties of biologically active compounds. A salen–scandium triflate complex-catalyzed asymmetric (3 + 2) annulation of dialkyl 1-sulfonylaziridine-2,2-dicarboxylates and aldehydes generated optically active functionalized oxazolidine derivatives in moderate to good yields and good to excellent

• method uses readily available salen as chiral ligand, which coordinates with scandium triflate to generate a salen–Sc complex acting as efficient catalyst. The catalytic asymmetric (3 + 2) annulation of dialkyl 3-aryl-1-sulfonylaziridine-2,2-dicarboxylates and aldehydes generated optically active

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