Experimental and DFT studies on the regioselective methanolysis of 5-azido-9-oxabicyclo[6.1.0]nonan-4-yl 4-nitrobenzoate isomers

• İlknur Polat,
• Selçuk Eşsiz and
• Emine Salamci

Beilstein J. Org. Chem. 2026, 22, 547–556, doi:10.3762/bjoc.22.40

• formed in both pathways. Free energy computations indicate that the intermediate 12 is thermodynamically more stable by 4.9 kcal mol−1 compared to intermediate 15. The nucleophilic attack by chloride ion bifurcates into two paths, namely C1- (route a) and C2-attacks (route b) for intermediates 12 and 15

• regioselectivity (Figure 4). In the protonated intermediate 12 derived from epoxide 9a, the carbon atom preferentially attacked by chloride bears a relatively more positive charge, which is consistent with an electronically favoured nucleophilic attack. In contrast, for the protonated intermediate 15 derived from

• epoxide 9b, the more positively charged epoxide carbon is sterically shielded by the neighbouring ester carbonyl group. As a result, nucleophilic attack occurs at the sterically more accessible, albeit less positively charged, epoxide carbon. These observations indicate that the regioselectivity of

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

• 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

• products were fused together by the nucleophilic attack of deprotonated alkyne 265 to aldehyde 261 (Scheme 31). The obtained diastereomers 266 were oxidized to the respective ketone 267, and again, Noyori reduction was performed to access 268 [105]. Treatment with AgBF4 at elevated temperature induced a

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

• ) intermediate, which undergoes intramolecular nucleophilic cyclization (Scheme 15) [54]. This work represents the first synthesis of a compound integrating both helical and axial stereogenic elements, and achieves high diastereoselectivity and enantioselectivity through a cinchona alkaloid-derived squaramide

• 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

• Discussion Chemistry Scheme 1 illustrates the synthesis of naphthalimide-organylselanyl conjugates 7 and 8. The incorporation of the organoselenide moiety into the naphthalimide scaffold was achieved via a nucleophilic substitution reaction. The bromine atom in the bromonaphthalimide precursor 12, prepared

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

• the fast increase of the molecular complexity, remains significant. Unlike the classical aminoethylation of nucleophilic compounds [28][29], Batey et al. recently developed a two-step approach consisted in addition of terminal ynimides I to various electrophiles with subsequent reduction of the C≡C

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

• geometry to the amide unit (Scheme 1a) [17][18][19]. As a result, nucleophilic attack at the carbonyl is disfavored, and even when a tetrahedral intermediate forms, collapse with expulsion of an amide anion is thermodynamically challenging. Consequently, harsh conditions such as high temperatures or

• of CeO2 to attack the carbonyl carbon, leading to cleavage of the C–N bond (B). Subsequent nucleophilic attack of the octoxide anion on the activated carbonyl center (C) then furnishes the ester product. Later, the same group found that niobium could also serve as a heterogeneous Lewis acid catalyst

• that coordination of the amide oxygen to the Lewis-acidic sites of Nb activates the amide toward nucleophilic attack. Simultaneously, water is pre-adsorbed on the basic oxygen sites of Nb2O5, enabling nucleophilic attack on the activated carbonyl center (D). Following amine release from the resulting

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

• -2-ethynylpyrrolidine-1-oxyls with nucleophilic agents can lead to the formation of condensed systems involving the substituent at position 3 of the pyrrolidine ring [16]. Alkynes are broadly used in the synthesis of various heterocyclic compounds, and participation of neighboring functional groups

• 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

• cyclopropyl system after nucleophilic attack by one of the olefins in 59. After a 1,2-hydride shift (59a to 59b) and nucleophilic capture of the tertiary cation to give 60, the full skeleton of tiglianes (e.g., phorbol (61)) would be assembled. An early example of a puzzling ring contraction observed in

• reactive pathway consists of an alkene isomerisation from the propenyl-substituent at C-5, followed by protonation of the C-7 alcohol to give intermediate 116a. From here a transannular cyclopropanation affords the cation 116b, which upon nucleophilic attack of water provides 116c. Expulsion of acetone

• formed by placing a leaving group on the C-5 tertiary hydroxy group of the precursor 138. This intermediate is privileged to undergo a 1,2-alkyl migration expanding the C-ring, giving a different decalin cation 138b. Keto/enol-tautomerism and nucleophilic attack of the enol at C-4/C-5 furnishes the

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

• disrupting the aromatic core, such as electrophilic and nucleophilic aromatic substitutions, transition metal-catalyzed cross-couplings [11], and C–H functionalizations [12]. Taken together with their natural abundance, these transformations have established arenes and heteroarenes as versatile synthetic

• during subsequent electrophilic addition. Although the trifluorotoluene complex exists as a mixture of its two coordination diastereomers, the pronounced electronic asymmetry of the molybdenum fragment channels protonation to a single η2-arenium intermediate. This enables nucleophilic addition of a

• dearomatization platform, combining pronounced π-basicity with practical scalability. Exploiting these attributes, a new multistep dearomatization protocol has recently been developed, enabling the conversion of arenes into trisubstituted cyclohexenes through three discrete nucleophilic additions to an η2-phenyl

A mild and atom-efficient four-component cascade strategy for the construction of biologically relevant 4-hydroxyquinolin-2(1H)-one derivatives

• Dmitrii A. Grishin,
• Kseniia I. Sharkovskaia,
• Ilya G. Kolmakov,
• Daria A. Ipatova,
• Rostislav A. Petrov,
• Nikolai D. Dagaev,
• Dmitry A. Skvortsov,
• Maria G. Khrenova,
• Valeriy V. Andreychev,
• Sergei A. Evteev,
• Yan A. Ivanenkov,
• Roman L. Antipin,
• Olga А. Dontsova and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2026, 22, 244–256, doi:10.3762/bjoc.22.18

• nucleophilic attack by the alcohol on the carbonyl group of the Meldrum’s acid fragment, thereby favoring formation of an open-chain ester rather than a lactone upon decarboxylation. Following this rationale, the reaction of 4-hydroxyquinolin-2-ones 2a–c, 3,4-dimethoxybenzaldehyde, and Meldrum’s acid in

• formation of the cyclic lactone, which predominated under such conditions. These findings suggest that intramolecular attack by the quinolinone OH group, leading to cyclization and formation of pyranoquinolinone, proceeds faster than nucleophilic attack by the external alcohol. Thus, under mild or brief

• products were also obtained via the four-component reaction using non-nucleophilic acetonitrile as solvent. However, this method requires subsequent purification by preparative chromatography, and, as noted, pyranoquinolines 14a–c readily undergo alcoholysis on silica columns with methanol-containing

Synthesis of diaryl phosphates using phytic acid as a phosphorus source

• Kazuya Asao,
• Seika Matsumoto,
• Haruka Mori,
• Riku Yoshimura,
• Takeshi Sasaki,
• Naoya Hirata,
• Yasuyuki Hayakawa and
• Shin-ichi Kawaguchi

Beilstein J. Org. Chem. 2026, 22, 213–223, doi:10.3762/bjoc.22.15

• phosphoric acid through a hydrolysis or E2 elimination reaction. The generated phosphoric acid forms a salt with triethylamine. Next, the phenoxy anion activated by the amine undergoes a nucleophilic attack on the phosphorus atom of the salt of phosphoric acid, resulting in the formation of MPP with the

• elimination of H2O. Then, two MPP molecules undergo a dehydration condensation reaction to form DPpyP [56]. Finally, the phenoxy anion undergoes a nucleophilic attack on the phosphorus atom of DPpyP, and DPP is formed through the elimination of MPP. In the absence of triethylamine, the esterification reaction

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

• 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

Base-promoted deacylation of 2-acetyl-2,5-dihydrothiophenes and their oxygen-mediated hydroxylation

• Vladimir G. Ilkin,
• Margarita Likhacheva,
• Igor V. Trushkov,
• Tetyana V. Beryozkina,
• Vera S. Berseneva,
• Vladimir T. Abaev,
• Wim Dehaen and
• Vasiliy A. Bakulev

Beilstein J. Org. Chem. 2026, 22, 192–204, doi:10.3762/bjoc.22.13

• phenols [25]. Hocking has described the oxidation of o-hydroxyacetophenone and some benzophenones with an aqueous alkaline hydrogen peroxide solution [26]. The key steps of oxidation of ketones into phenols include: a) nucleophilic addition of the hydroperoxide anion to the carbonyl carbon; b) [1,2]-aryl

Streptoquinolines A and B, new antibacterial meroterpenoids produced by Streptomyces sp. TMPU-A0679

• Akiho Yagi,
• Hitomi Tomura,
• Ami Konno and
• Ryuji Uchida

Beilstein J. Org. Chem. 2026, 22, 185–191, doi:10.3762/bjoc.22.12

• acetone; therefore, they may be artifacts that formed via the nucleophilic addition of acetone to a ketone-bearing precursor during the extraction process. Despite various modifications to fermentation conditions, it was not possible to detect or isolate the presumed natural precursor. We are currently

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

• -bromosuccinimide to generate a highly electrophilic sulfilimidoyl bromide intermediate R–S(Br)=N–C(O)R’, along with succinimide. The resulting S(IV)–Br species is then attacked by the alcohol 2, and nucleophilic substitution at sulfur followed by proton transfer furnishes the sulfinimidate ester 3 and HBr. The

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

• Mannich reaction between a 2-sulfonylpyridine protected imine and a malonate (Scheme 1). The pyridine-containing protecting group was chosen considering our catalyst design. We envisioned that halogen bond (XB) will complement hydrogen bonds to activate an imine towards the nucleophilic attack of the

Symmetrical D–π–A–π–D indanone dyes: a new design for nonlinear optics and cyanide detection

• Ergin Keleş,
• Alberto Barsella,
• Nurgül Seferoğlu,
• Zeynel Seferoğlu and
• Burcu Aydıner

Beilstein J. Org. Chem. 2026, 22, 131–142, doi:10.3762/bjoc.22.6

• ). The vinyl bridges were added to the design, which have the potential to open nucleophilic addition reactions (Michael type) due to their electron deficiencies, in addition to acting as π-bridges for the D–A conjugation. Furthermore, a symmetric design with increased π-conjugation was planned to shift

• detect cyanide anions due to the presence of vinyl groups, where cyanide can be attacked via nucleophilic addition reaction. Therefore, the sensitivity and selectivity of dyes towards cyanide were investigated by the addition of cyanide (CN−) and competing anions (F−, Cl−, Br−, I−, AcO−, ClO4−, H2PO4

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

• 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

• -tetrahydroisoquinoline natural products, (±)-lemonomycinone and (±)-renieramycin, featuring as key steps a dearomative nucleophilic addition and diastereoselective hydrogenation of a dihydroisoquinoline (Scheme 16) [85]. Starting from pentasubstituted isoquinoline 117, the authors utilized a dearomative nucleophilic

• through sequential nucleophilic attack and intramolecular cyclization. (+)-Isomatrine was subsequently synthesized through catalytic hydrogenation via Rh/C, LAH reduction, and tertiary amine oxidation (Scheme 28). After synthesizing (+)-isomatrine, the effects of catalyst type, loading, temperature, and

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

• reactions mainly involve the initial electrophilic attack onto the α-position relative to the hydrogen atom. The selectivity is either due to the high stability of the α-nucleophilic conformer or due to the promotion by the adjacent ester group. Cascade reactions upon the target connection, if installed

• planarity of the two neighboring ester groups and thereby stabilize the anion. The prevalence of this isomer is also confirmed by the NMR data [21], however, other conformers with different charge distributions are also available in solution. To understand the nucleophilic reactivity of the most stable

• revealed that the α-position is most nucleophilic. Notably, anion 1 demonstrated similar HOMO and Fukui function distribution (see Supporting Information File 1), however, all positions would lead to the very same products. The potassium salt of anion 2 was generated in an acetonitrile solution from hexa

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

• ). Importantly, a lower alkyne-to-chloride ratio resulted in diminished yields of 155. The authors proposed that the key intermediate is a linear vinyl cation with a planar geometry (217, Scheme 40B), wherein the empty p-orbital lies in the molecular plane. As such, nucleophilic attack occurs within this plane

• 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

One-pot synthesis of ethylmaltol from maltol

• Immanuel Plangger,
• Marcel Jenny,
• Gregor Plangger and
• Thomas Magauer

Beilstein J. Org. Chem. 2025, 21, 2755–2760, doi:10.3762/bjoc.21.212

• less nucleophilic and sterically more hindered base lithium diisopropylamide (LDA), the yield of ethylmaltol (1) increased to 25% and maltol (2) was recovered in 17% (Table 1, entry 3). Notably, treatment of maltol (2) with LDA resulted in a deep purple solution with no apparent solubility issues. We

• nucleophilicity of the intermediate lithium alkoxides and to the softer nucleophilic character at C vs O for lithium dienolates. While the dianion strategy was able to convert maltol (2) to ethylmaltol (1) in yields of up to 57%, the reactions suffered from an unsatisfactory purity profile. First, interconversion

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

Competitive cyclization of ethyl trifluoroacetoacetate and methyl ketones with 1,3-diamino-2-propanol into hydrogenated oxazolo- and pyrimido-condensed pyridones

• Svetlana O. Kushch,
• Marina V. Goryaeva,
• Yanina V. Burgart,
• Marina A. Ezhikova,
• Mikhail I. Kodess,
• Pavel A. Slepukhin,
• Alexandrina S. Volobueva,
• Vladimir V. Zarubaev and
• Victor I. Saloutin

Beilstein J. Org. Chem. 2025, 21, 2716–2729, doi:10.3762/bjoc.21.209

• , 620066 Ekaterinburg, Russian Federation Saint-Petersburg Pasteur Institute, Mira St. 14, 197101 Saint-Petersburg, Russian Federation 10.3762/bjoc.21.209 Abstract The use of 1,3-diamino-2-propanol with competitive N- and O-nucleophilic centers in a three-component cyclization with ethyl 4,4,4

• for 3-polyfluoroalkyl-3-oxo esters containing an activated carbonyl group capable of adding α-methylene ketones. It is characterized by the cyclization at the 1,3-dicarbonyl fragment of 3-oxo ester and offers a possibility of using a variety of nucleophilic agents to form hydrogenated diastereomeric

• three nucleophilic centers in 1,3-diaminopropan-2-ol (3), and because there is a need to increase diastereoselectivity of the cyclization process. Table 1 presents the optimization steps for the reaction conditions at various solvents and temperature. The reaction course was monitored by TLC and 19F NMR

Mechanistic insights into hydroxy(tosyloxy)iodobenzene-mediated ditosyloxylation of chalcones: a DFT study

• Jai Parkash,
• Sangeeta Saini,
• Vaishali Saini,
• Omkar Bains and
• Raj Kamal

Beilstein J. Org. Chem. 2025, 21, 2703–2715, doi:10.3762/bjoc.21.208

• )3/CH3OH, PhI(OCOCH3)2/CH3OH and PhI(OH)OTs/CH3OH in polar nucleophilic solvents [24][25][26][27][28]. A number of experimental and computational studies have explored the reaction pathway for these oxidative rearrangement reactions under metal-free conditions with the use of hypervalent iodine(III

• ) compounds in polar nucleophilic or non-nucleophilic solvents [10][11][12][20][29][30][31][32][33][34][35][36]. Fujita discusses typical pathways of alkene oxidation with hypervalent iodine in great detail including the stereochemical course of reaction involving a cyclic iodonium ion [30]. In the literature

• differences as given in parenthesis for all studied substituents including -OCH3. Overall both in Scheme 2 and Scheme 3, the reaction between chalcone and HTIB proceeds through electrophilic addition of [PhIOH]+ followed by nucleophilic addition of −OTs. In the beginning electrophilic addition occurs on the