Kinetic resolution of racemic planar-chiral vinylcymantrenes by molybdenum-catalyzed asymmetric metathesis dimerization

• Haruna Imazu,
• Hitoshi Izu,
• Yasuhiro Ohki and
• Masamichi Ogasawara

Beilstein J. Org. Chem. 2026, 22, 568–574, doi:10.3762/bjoc.22.42

• (I). Indeed, the Friedel–Crafts acetylation of cymantrene, a typical electrophilic aromatic substitution reaction, is much slower than that of ferrocene. Consequently, vinylcymantrenes are electron-deficient olefins and less reactive in olefin metathesis. For this reason, the present AMD/KR reactions

Get a better glimpse on sequential photoreactions of trisnorbornadienes with ¹⁹F NMR spectroscopy

• Julian Felix Maria Hebborn,
• Ben Eric Merten,
• Thomas Paululat and
• Heiko Ihmels

Beilstein J. Org. Chem. 2026, 22, 527–534, doi:10.3762/bjoc.22.38

• hindrance induced by the fluoro substituents in the ortho positions [54]. It should be noted that there is only very limited data available to compare the effect of the substitution pattern on the half-life of aryl-substituted norbornadienes to support this interpretation [55]. However, the effect of ortho

Modern synthetic pathways towards eribulin and its subunits

• Sebastian Dominik Graf

Beilstein J. Org. Chem. 2026, 22, 495–526, doi:10.3762/bjoc.22.37

• –Kishi (NHK) coupling and Pd-mediated cyclization. Fragment 31 was synthesized from known precursor 28 [74] in 9 steps via MMTr-protection, replacement of the Bn- with TBDMS-protecting groups, hydroxylation of sulfone 29 to alcohol 30, tosylation, bromide substitution, acidic MMTr-cleavage and DMP

• )/Cr(II)-mediated coupling of 1-bromo-2-trimethylsilylethene, acidic cleavage of the remaining cyclohexylidene ring, TBDMS-protection of the three alcohol units and electrophilic substitution of the silyl moiety to afford vinyl iodide 103 was applied. Eventually, ester 103 was reduced to target

• formation of 252. Next, conditions reported by Kishi and co-workers were applied for the nucleophilic substitution of the chloride by the oxygen from the tetrahydrofuran ring towards 253 [94], before an adjacent secondary alcohol group reopened the bicyclic cationic intermediate. Cleavage of the TBDMS

Recent advances in the stereoselective synthesis of distal biaxially chiral molecules

• Fanxing Zhou,
• Chen Zhang,
• Lingyu Sun,
• Yiyun Fang,
• Siming Zheng,
• Lina Hu,
• Mengyang Shen,
• Zhen Zhao,
• Wei Xu,
• Yunqiang Sun and
• Zi-Qiang Rong

Beilstein J. Org. Chem. 2026, 22, 461–479, doi:10.3762/bjoc.22.34

• carboxylic acid derivatives (Scheme 2b) [43]. They revealed that ortho-alkoxy substitution on the benzene-derived alkyne markedly enhanced both reactivity and enantioselectivity, while incorporation of a naphthyl substituent into the diyne enabled access to remote biaxially chiral molecules. Subsequent

• first enantioselective C–H amination of arenes catalyzed by a chiral phosphoric acid. Thus, this nucleophilic aromatic substitution reaction not only enables the synthesis of compounds bearing two chiral N-aryl axes but also provides a viable alternative to metal-catalyzed C–N cross-coupling reactions

Synthesis and anti-cancer activity of naphthalimide–organylselanyl conjugates

• Rajkumar Ravi and
• Selvakumar Karuthapandi

Beilstein J. Org. Chem. 2026, 22, 416–435, doi:10.3762/bjoc.22.29

• major strategy involves fused-ring modification, wherein heteroatoms such as azo or thiol groups are introduced either linearly at the 4,5-position or laterally at the 5,6-position of the naphthalimide ring [32][33][34][35][36][37]. A second approach involves positional substitution, shifting functional

• enhancing lysosomal membrane permeability and aqueous solubility [42]. Interestingly, for the first time, N-(n-octyl) chain substitution has been shown to demonstrate remarkable anticancer activity, particularly through tyrosine kinase inhibition, without significant DNA intercalation [43]. Among these

• derivatives, N-(n-octyl) substitution at the 6-position exhibits a more pronounced effect as compared to octyl substitutions linked to the imide nitrogen of the naphthalimide ring [44]. Furthermore, comparative studies between sulfur- and selenium-containing naphthalimide analogues revealed that the selenium

Cone p-aminocalix[4]arenes enriched with ‘clickable’ alkyne or azide functionalities

• Ilia Korniltsev,
• Vasily Bazhenov,
• Alexander Gorbunov,
• Dmitry Cheshkov,
• Stanislav Bezzubov,
• Vladimir Kovalev and
• Ivan Vatsouro

Beilstein J. Org. Chem. 2026, 22, 399–415, doi:10.3762/bjoc.22.28

• substitution patterns were selected as the starting materials to enable further preparation of the respective mono-, di- and tetrapropargylated calix[4]arene tetraamines and their derivatives. The silylation of propargyl ethers 1–5 was first attempted using tert-butyldimethylsilyl chloride (TBSCl) and the

• conditions. In line with this, compounds 8–10 having less sterically hindered narrow-rim substitution patterns were found to be more resistant to side reactions during wide-rim nitration as well as to the target exhaustive nitration itself. These reactions required a higher nitric acid concentration of ≈2.5

• only the reaction time increased (Scheme 2). The 1D NMR spectra for the dinitrocalix[4]arenes 12 and 13 provided no definitive data on the substitution patterns at their wide-rims except for the presence of two nitro groups in the distal aromatic units. To localize the nitro groups in the structures of

Design, synthesis and biological evaluation of 2,5-diaryloxazolo[4,5-d]pyrimidin-7-ylamines as selective cytotoxic agents against HeLa cells

• Maryna V. Kachaeva,
• Agnieszka B. Olejniczak,
• Marta Denel-Bobrowska,
• Victor V. Zhirnov,
• Yevheniia S. Velihina,
• Stepan G. Pilyo and
• Volodymyr S. Brovarets

Beilstein J. Org. Chem. 2026, 22, 390–398, doi:10.3762/bjoc.22.27

• therapeutic potential. Analyzing the structure–activity relationship with respect to the HeLa cancer cell line, it can be seen that among the diphenyloxazolopyridine derivatives, the substitution of the piperidine functional motif at position 7 in compound 1 by 4-ethylpiperazine leads to a decrease in the

• cytotoxicity by two times (compound 3). Whereas its substitution by morpholine lead to inactive compound 2. The same result was obtained by substituting 2-piperidin-1-ylpropylamine in 1 with hexahydro-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (6). However, methylation of the phenyl group at the 5-position of

• addition of a 4-chlorophenyl group instead of the methyl group as a functional motif at position 7 (4) sharply reduced the cytotoxicity of compound 1. The substitution of piperidine by morpholine in this motif in compound 4 resulted in a 2-fold increase in the activity of the obtained derivative 5. However

Dialkylaminoalkylation of β-ketosulfones via ring-opening of 3-sulfonylpyrrolidines

• Evgeny M. Buev,
• Alexander V. Pavlushin,
• Vladimir S. Moshkin and
• Vyacheslav Y. Sosnovskikh

Beilstein J. Org. Chem. 2026, 22, 383–389, doi:10.3762/bjoc.22.26

• obtained products with LiAlH4 leads to a substitution of the attached nucleophilic moiety with hydrogen in good yields. Keywords: aminoalkylation; aminosulfones; ketosulfones; pyrrolidines; Introduction Sulfones and sulfonic acids are valuable structural motifs in organic chemistry, notable for their

• commonly achieved by a classic nucleophilic substitution of a leaving group at the β-position relative to the N-protected nitrogen (Figure 2a). While this approach addresses most needs of targeted synthesis, developing alternative methods from inexpensive starting materials via domino-processes, allowing

Electrosynthetic access to unsymmetrical oxaza[8]helicenes with high chiral stability and strong circularly polarized luminescence (CPL)

• Tin Zar Aye,
• Rubal Sharma,
• Muthu Karuppasamy,
• Daiya Suzuki,
• Haruka Nakajima,
• Yoshitane Imai,
• Mitsuhiro Arisawa,
• Mohamed S. H. Salem and
• Shinobu Takizawa

Beilstein J. Org. Chem. 2026, 22, 372–382, doi:10.3762/bjoc.22.25

• hand, the brightness BCPL values were calculated to be 30.75 M−1 cm−1 for 5b and 31.46 M−1 cm−1 for 6b. This comprehensive understanding of the influence of phenyl substitution and helical extension on the CPL features of oxaza[n]helicenes provides a valuable roadmap for designing future CPL- emitters

Recent advances in the cleavage of non-activated amides

• Eun-Sol Choi and
• Hyo-Jun Lee

Beilstein J. Org. Chem. 2026, 22, 352–369, doi:10.3762/bjoc.22.23

• a major objective in contemporary synthetic chemistry [12][13][14][15][16]. Despite their ubiquity, amides are notoriously unreactive toward classical acyl-substitution pathways. This inertness arises from a strong amidic resonance, which confers partial C=N double-bond character and a planar

• % yield. Mechanistically, WCl6 coordinates with Phen to generate the active tungsten species [G]. In cooperation with TMSCl as a Lewis acid, the catalyst activates the amide toward nucleophilic attack by forming an electron-deficient intermediate H that readily undergoes substitution. Palladium complexes

• of 2 equivalents of TCCA as a chlorinating reagent and 2.5 equivalents of lithium benzoate (LiOBz) as a base, primary amides are converted into the corresponding N,N-dichloroamide intermediates 46, which then undergo smooth nucleophilic acyl substitution with alcohols to afford esters. The substrate

Synthesis of tricyclic fused pyrrolidine nitroxides from 2-alkynylpyrrolidine-1-oxyls

• Mark M. Gulman,
• Yuliya F. Polienko,
• Sofia Yu. Trakhininа,
• Yuri V. Gatilov,
• Tatyana V. Rybalova,
• Sergey A. Dobrynin and
• Igor A. Kirilyuk

Beilstein J. Org. Chem. 2026, 22, 344–351, doi:10.3762/bjoc.22.22

• literature data on reactivity of 5-azidopentyne derivatives in intramolecular Huisgen cycloaddition reactions are contradictory. Some authors successfully obtained 5-azidopentyne derivatives upon nucleophilic substitution at 80 °C in DMF, and additional heating at 170 °C was necessary for cyclization to

Ring contraction and ring expansion reactions in terpenoid biosynthesis and their application to total synthesis

• Nicolas Kratena,
• Nicolas Heinzig and
• Peter Gärtner

Beilstein J. Org. Chem. 2026, 22, 289–343, doi:10.3762/bjoc.22.21

• that, in analogy to related compounds 114 and 131, an initial oxidative event at C-17 (145a) results in the 1,2-methyl group shift (see Scheme 35A). Capture of the tertiary carbocation by a peroxy-species would deliver 145b, which upon C-11 hydroxylation and SN’ substitution by the hydroperoxide could

Spirobarbiturates with a pyrrolizidine moiety: synthesis, structure and biological evaluation

• Arthur A. Puzyrkov,
• Andrew S. Drachuk,
• Ekaterina A. Popova,
• Alexander V. Stepakov and
• Vitali M. Boitsov

Beilstein J. Org. Chem. 2026, 22, 274–288, doi:10.3762/bjoc.22.20

• ). Substitution of the meta-chlorine with fluorine also favored the exo-isomer (compound 4j, 70%, endo/exo 1:2), similar to 4l. The presence of an electron-withdrawing group at the meta-position of the maleimide’s N-aryl group likely facilitates exo-isomer formation. Reactions with maleimides containing meta-NO2

• -halogen substitution in aromatic maleimides was found to preferentially direct the cycloaddition toward the formation of exo-isomers. The structures of all obtained diastereomers were thoroughly characterized by 1H and 13C NMR spectroscopy. Single crystal XRD analysis of two representative compounds

Arene activation via π-bond localization: concepts and opportunities

• Paul Meiners,
• Julian J. Melder and
• Tobias Morack

Beilstein J. Org. Chem. 2026, 22, 257–273, doi:10.3762/bjoc.22.19

• also profoundly influences the electronic character of the aromatic ring. The ring becomes more electron-rich, akin to substitution with electron-donating groups, and exhibits distinct distortions in the bond lengths of the ring, consistent with localization of the π-system (i.e., dearomatization

• , display remarkable substitution inertness, even toward strong π-acids and good σ-donors. The substitution rate being relatively independent of the incoming ligand is consistent with a dissociative substitution mechanism. Typically, coordination occurs at positions that minimally disrupt the arene π-system

• metal center with α-pinene and subsequent ligand substitution proceeds with retention of configuration, the corresponding Mo(0) complex undergoes racemization during substitution (Scheme 2A). This obstacle was overcome by a redox-based approach: oxidation of the Mo(0)–α-pinene complex with iodine to a

Conformational analysis of difluoromethylornithine: factors influencing its gas-phase and bioactive conformations

• Matheus P. Freitas

Beilstein J. Org. Chem. 2026, 22, 237–243, doi:10.3762/bjoc.22.17

• decarboxylase and as a therapeutic agent against African trypanosomiasis. Beyond its pharmacological importance, DFMO provides a valuable model for examining how fluorine substitution governs molecular conformation. A comprehensive quantum-chemical study was performed to elucidate the origins of DFMO’s

Screwing the helical chirality through terminal peri-functionalization

• Devesh Chandra,
• Sachin and
• Upendra Sharma

Beilstein J. Org. Chem. 2026, 22, 205–212, doi:10.3762/bjoc.22.14

• substitution pattern along the plane of symmetry, is known as planar chirality, as seen in metallocene and cyclophanes. Molecules containing planar chirality have greater relevance in materials science and stereoselective transformations [12][13]. The fourth branch of the chiral tree is helical chirality. A

• nucleophilic substitution reactions (Scheme 5). A stereochemical model was proposed for the phospha-Michael addition, indicating that enantioselectivity was primarily influenced by steric effects arising from hydrogen bonding and ion pairing between the peptide mimetic phosphonium salt (PPS)-activated

Improved synthesis and physicochemical characterization of the selective serotonin 2A receptor agonist 25CN-NBOH

• Adrian G. Rossebø,
• Hannah G. Kolberg,
• Anders E. Tønder,
• Louise Kjaerulff,
• Poul Erik Hansen,
• Karla A. Frydenvang,
• Jesper Østergaard and
• Jesper L. Kristensen

Beilstein J. Org. Chem. 2026, 22, 175–184, doi:10.3762/bjoc.22.11

• effect is a clear indication that the OH group is engaged in an IMHB [19]. Furthermore, the relatively small isotope effect on C11 and C12 also indicates a hydrogen bond to nitrogen (i.e., nitrogen as hydrogen bond acceptor), as the effect caused solely by NH(D) substitution would have been expected to

A new synthesis of Tyrian purple (6,6’-dibromoindigo) and its corresponding sulfonate salts

• Holly Helmers,
• Mark Horton,
• Julie Concepcion,
• Jeffrey Bjorklund and
• Nicholas C. Boaz

Beilstein J. Org. Chem. 2026, 22, 167–174, doi:10.3762/bjoc.22.10

• Scheme 5A, dimethyl sulfoxide (DMSO) did not react with the benzyl bromide and instead only returned the starting material. The addition of 1.2 equivalents of silver nitrate promoted the substitution of the benzyl bromide with DMSO to yield an alkoxysulfonium ion 8 [22]. Following substitution, the

Circumventing Mukaiyama oxidation: selective S–O bond formation via sulfenamide–alcohol coupling

• Guoling Huang,
• Huarui Zhu,
• Shuting Zhou,
• Wanlin Zheng,
• Fangpeng Liang,
• Zhibo Zhao,
• Yifei Chen and
• Xunbo Lu

Beilstein J. Org. Chem. 2026, 22, 158–166, doi:10.3762/bjoc.22.9

• , indicating partial stereochemical transfer from the chiral alcohol. We next investigated the stereochemical outcome of the Grignard substitution using diastereomeric sulfilimidate ester 5 (dr = 1.6:1), derived from ʟ-menthol. When treated with MeMgI, product 6a was obtained in 88% yield but with no

• enrichment of one enantiomer in the product mixture. To further probe this possibility, the two diastereomers of 5 were carefully separated and individually subjected to Grignard substitution. Reactions of the isolated diastereomers with MeMgI and PhMgBr afforded 6a-1 and 6b-1 with 92% ee and 93% ee

• , respectively (see the Supporting Information File 1 for more details). These results demonstrate that each diastereomer undergoes substitution with high stereospecificity. The moderate ee observed in the reaction of the diastereomeric mixture can therefore be rationalized by the differing intrinsic

Asymmetric Mannich reaction of aromatic imines with malonates in the presence of multifunctional catalysts

• Kadri Kriis,
• Harry Martõnov,
• Annette Miller,
• Mia Peterson,
• Ivar Järving and
• Tõnis Kanger

Beilstein J. Org. Chem. 2026, 22, 151–157, doi:10.3762/bjoc.22.8

• petroleum ether/Et2O (see the Experimental section). Generally, the reactions are fast and afford products in high to excellent enantiomeric purities. The substitution pattern in the phenyl ring has some influence on the results (compare compounds 3a–d). The ortho-Cl substituent in the aromatic ring of 1b

Highly electrophilic, gem- and spiro-activated trichloromethylnitrocyclopropanes: synthesis and structure

• Ilia A. Pilipenko,
• Mikhail V. Grigoriev,
• Olga Yu. Ozerova,
• Igor A. Litvinov,
• Darya V. Spiridonova,
• Aleksander V. Vasilyev and
• Sergey V. Makarenko

Beilstein J. Org. Chem. 2026, 22, 123–130, doi:10.3762/bjoc.22.5

• to the bromonitroalkene afford the intermediate anion II, followed by tautomerization and formation of anion IV, which undergoes intramolecular nucleophilic substitution of the bromide along the C-alkylation pathway [37][38][39] (Scheme 6). The trans-configuration of the methine protons of the

Total synthesis of natural products based on hydrogenation of aromatic rings

• Haoxiang Wu and
• Xiangbing Qi

Beilstein J. Org. Chem. 2026, 22, 88–122, doi:10.3762/bjoc.22.4

• ][19][20]. In recent years, promoted by the rapid development of asymmetric catalysis, a wealth of reactions applicable to aromatic systems – including substitution reactions, transition-metal-coupling reactions, and even dearomatization [21][22][23] – have been reported, further extending their

• chloride. Finally, through a sequence of removal of the Cbz protecting group, alcohol chlorination, proximal nucleophilic substitution, and deprotection of the secondary alcohol, the first total synthesis of nominine was completed. Although the synthetic route seemed to be lengthy, this challenging total

Reactivity umpolung of the cycloheptatriene core in hexa(methoxycarbonyl)cycloheptatriene

• Dmitry N. Platonov,
• Alexander Yu. Belyy,
• Rinat F. Salikov,
• Kirill S. Erokhin and
• Yury V. Tomilov

Beilstein J. Org. Chem. 2026, 22, 64–70, doi:10.3762/bjoc.22.2

• providing additional reaction pathways such as in bicyclobutanes (Figure 1) [7]. An umpolung approach was previously used in α-substitution of tropone [8]. Cycloheptatrienes are commonly expected to generate aromatic tropylium ions. Tropylium ions are so stable that they are formed not only through leaving

• reported [31] halogenations of anion 1 only afforded the corresponding octasubstituted cycloheptatriene derivatives. The reactions of 2 with alkyl halides were selective in terms of the initial reaction – the i-substitution was never observed. However, the alkylation reactions were even more intricate than

• sterically hindered 2-(methoxycarbonyl)phenyldiazonium ion afforded only one isomer of dihydroindazole 8k which indicates the influence of the steric factor on the azocyclopropane rearrangement. However, the reaction additionally gave the product of an i-substitution with subsequent proton migration to form

Synthesis and applications of alkenyl chlorides (vinyl chlorides): a review

• Daniel S. Müller

Beilstein J. Org. Chem. 2026, 22, 1–63, doi:10.3762/bjoc.22.1

• Finkelstein-type halide exchange reaction (Scheme 23). This strategy leverages the decreasing bond-dissociation energies across the halogen series – C–Cl (D298(C−Cl) = 395 kJ mol−1) and C–Br (D298(C–Br) = 318 kJ mol−1) bonds compared to the C–I bond (D298(C–I) = 253 kJ mol−1) to drive the substitution of

• nucleophilic chloromethylenetitanium species that transforms a ketone into the corresponding alkenyl chlorides (Scheme 63) [199]. 1.10 Allylic substitutions Allylic substitution of readily accessible alkenyl chlorides bearing a suitable leaving group at the allylic position enables efficient introduction of

• the alkenyl chloride motif. Scheme 64, depicts representative examples by Boger [200], Taber [201], and Morken [202]. In 2012, Feringa and co-workers reported the first enantioselective allylic substitution of allylic gem-dichlorides with alkyl Grignard reagents (Scheme 65A) [203]. The reaction

Sustainable electrochemical synthesis of aliphatic nitro-NNO-azoxy compounds employing ammonium dinitramide and their in vitro evaluation as potential nitric oxide donors and fungicides

• Alexander S. Budnikov,
• Nikita E. Leonov,
• Michael S. Klenov,
• Andrey A. Kulikov,
• Igor B. Krylov,
• Timofey A. Kudryashev,
• Aleksandr M. Churakov,
• Alexander O. Terent’ev and
• Vladimir A. Tartakovsky

Beilstein J. Org. Chem. 2025, 21, 2739–2754, doi:10.3762/bjoc.21.211

• nucleophilic substitution of –ONO2 groups. To clarify the reaction mechanism, cyclic voltammetry (CV) studies were conducted. CV curves of cyclohexanone oxime (S1), 1-bromo-1-nitrosocyclohexane (S2), 1-chloro-1-nitrosocyclohexane (S3), 1-nitrosocyclohexyl acetate (S4), 1-nitro-1-nitrosocyclohexane (1c), 1