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

Tandem hydrothiocyanation/cyclization of CF₃-iminopropargyl alcohols with NaSCN in the presence of AcOH

• Ruslan S. Shulgin,
• Ol’ga G. Volostnykh,
• Anton V. Stepanov,
• Igor’ A. Ushakov,
• Alexander V. Vashchenko and
• Olesya A. Shemyakina

Beilstein J. Org. Chem. 2025, 21, 2694–2702, doi:10.3762/bjoc.21.207

• different cyclizations due to the conjugated imine and alkyne bonds [27], and the hydroxyalkyl moiety linked to the triple bond can also act as a nucleophilic site. Another attractive feature of these compounds is the presence of the trifluoromethyl group (CF3). The latter serves as a valuable structural

• nucleophilic center – imino group or an imino and OH groups. The synthesized compounds are potential drug precursors, synthons, and multipurpose building blocks for fine organic synthesis. We believe that the present method will be of significant interest to synthetic and medicinal chemists due to the

Recent advancements in the synthesis of Veratrum alkaloids

• Morwenna Mögel,
• David Berger and
• Philipp Heretsch

Beilstein J. Org. Chem. 2025, 21, 2657–2693, doi:10.3762/bjoc.21.206

• introduced by addition of 2-lithio-5-methylpyridine (94) to methyl ketone 93, with the major addition product 95 exhibiting the desired configuration at C20. Tosylation of the primary C18–OH in 95 (and secondary C3–OH) was followed by intramolecular nucleophilic substitution through the pyridine nitrogen

Thiazolidinones: novel insights from microwave synthesis, computational studies, and potentially bioactive hybrids

• Luan A. Martinho,
• Victor H. J. G. Praciano,
• Guilherme D. R. Matos,
• Claudia C. Gatto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2025, 21, 2618–2636, doi:10.3762/bjoc.21.203

• ], antioxidant [34], cytotoxic [35], and antiproliferative [36]. The structures of these compounds allow the synthesis of a large collection of bioactive molecules due to their nucleophilic and electrophilic properties [37]. One of the forms of modifications is at the methylene group, particularly in the 5

• disubstitution processes involving sulfur-to-nitrogen displacement, likely promoted by the nucleophilic character of the amine. These limitations are likely due to the reaction conditions employed, including the high temperature and acidic environment, which may favor side reactions over the desired

Visible-light-driven NHC and organophotoredox dual catalysis for the synthesis of carbonyl compounds

• Vasudevan Dhayalan

Beilstein J. Org. Chem. 2025, 21, 2584–2603, doi:10.3762/bjoc.21.200

• -rich and electron-poor substituents. This reaction was carried out between arylcyclopropanes 5 and acyl fluoride 4 in the presence of NHC (10 mol %) and 4CzIPN (5 mol %). Mechanistic studies showed that the cascade proceeds via nucleophilic ring-opening of a cyclopropyl radical cation D with subsequent

• system involves the efficient nucleophilic addition of an imidazolyl anion B to radical cation species A, generated via single-electron oxidation of electron-donating arenes 31. The azolide anion B is released from acylimidazole 9 through an addition/elimination sequence in the presence of an NHC

Recent advances in total synthesis of illisimonin A

• Juan Huang and
• Ming Yang

Beilstein J. Org. Chem. 2025, 21, 2571–2583, doi:10.3762/bjoc.21.199

• , deprotonation, and intramolecular addition to ketone. Treatment of the silacycle with MeMgCl cleaved the Si–O bond and subsequent intramolecular nucleophilic substitution of the chloride with the adjacent hydroxy group yielded TMS-epoxide 41. Protonic acid-mediated opening of the TMS-epoxide, accompanied by TES

Assembly strategy for thieno[3,2-b]thiophenes via a disulfide intermediate derived from 3-nitrothiophene-2,5-dicarboxylate

• Roman A. Irgashev

Beilstein J. Org. Chem. 2025, 21, 2489–2497, doi:10.3762/bjoc.21.191

• . Nucleophilic substitution of the nitro group with sulfur nucleophiles, including thioacetate or disulfide anions as well as thioacetamide, yielded bis(thiophen-3-yl)disulfide and sulfide derivatives. The disulfide served as a suitable precursor for the preparation of 3-alkylthio-substituted thiophene-2,5

• functionalized thieno[3,2-b]thiophenes with potential applications in pharmaceutical and materials chemistry. Keywords: aromatic nucleophilic substitution; disulfide derivative; 3-nitrothiophene; organic disulfides; thieno[3,2-b]thiophene; thiophene ring closure; Introduction Thieno[3,2-b]thiophene (TT

• K2CO3 in DMSO to give the desired product [26]. Route III, previously elaborated in our group, utilizes the nucleophilic substitution of the Cl atom in 3-chlorothiophene-2-carboxylates by methyl thioglycolate in the presence of KOt-Bu, followed by KOt-Bu-mediated cyclization to the 3-hydroxy-TTs [27

Synthesis of the tetracyclic skeleton of Aspidosperma alkaloids via PET-initiated cationic radical-derived interrupted [2 + 2]/retro-Mannich reaction

• Ru-Dong Liu,
• Jian-Yu Long,
• Zhi-Lin Song,
• Zhen Yang and
• Zhong-Chao Zhang

Beilstein J. Org. Chem. 2025, 21, 2470–2478, doi:10.3762/bjoc.21.189

• leads to ketene D, which can undergo cycloaddition with an alkene to yield E. This fragmentation pathway dominates under various conditions (e.g., transition-metal catalysis, nucleophilic addition) and is driven by ring-strain release [11]. PET, an alternative to direct excitation and EnT, enables the

Catalytic enantioselective synthesis of selenium-containing atropisomers via C–Se bond formations

• Qi-Sen Gao,
• Zheng-Wei Wei and
• Zhi-Min Chen

Beilstein J. Org. Chem. 2025, 21, 2447–2455, doi:10.3762/bjoc.21.186

• formation proceeded through an SN2-type nucleophilic substitution mechanism (Scheme 1). In 2025, Li and co-workers reported a highly efficient rhodium-catalyzed enantioselective C–H selenylation reaction of 1-arylisoquinolines with diselenides, employing 3,5-(CF3)2C6H3CO₂Ag and AgSbF6 as additives [19

• phenyl-substituted benzoisoquinoline derivatives. Two plausible reaction mechanisms were proposed in the study: one involving oxidative addition of Int 4, a five-membered rhodium cyclic intermediate, followed by reductive elimination and the other proceeding via a bimolecular nucleophilic substitution

• .1 initially engages substrate 7 through hydrogen bonding, forming intermediate Int 7. Subsequently, deprotonation of the naphthol group by quinuclidine yields intermediate Int 8. This intermediate then undergoes nucleophilic attack on the selenium atom in substrate 8, leading to the formation of the

Transformation of the cyclohexane ring to the cyclopentane fragment of biologically active compounds

• Natalya Akhmetdinova,
• Ilgiz Biktagirov and
• Liliya Kh. Faizullina

Beilstein J. Org. Chem. 2025, 21, 2416–2446, doi:10.3762/bjoc.21.185

• converted by a series of synthetic transformations to (−)-spirochensilide A (228) with a total yield of 2.2% in 22 steps starting from acetylenic epoxide 229. 4.1 Wagner–Meerwein rearrangement The isomerization of terpenes via cleavage, addition or nucleophilic substitution reactions accompanied by a

Rotaxanes with integrated photoswitches: design principles, functional behavior, and emerging applications

• Jullyane Emi Matsushima,
• Khushbu,
• Zuliah Abdulsalam,
• Udyogi Navodya Kulathilaka Conthagamage and
• Víctor García-López

Beilstein J. Org. Chem. 2025, 21, 2345–2366, doi:10.3762/bjoc.21.179

• methoxide anion (Figure 2). The neutral acridane is restored through the thermal nucleophilic attack of the alkoxide on the acridinium ion. Abraham and co-workers exploited this dramatic change in the electronic nature and geometric shape of acridane to modulate the translation of cyclobis(paraquat-4,4

Comparative analysis of complanadine A total syntheses

• Reem Al-Ahmad and
• Mingji Dai

Beilstein J. Org. Chem. 2025, 21, 2334–2344, doi:10.3762/bjoc.21.178

• hemiaminal opening and amine–ketone condensation, iminium ion 65 was produced for the next pyrrole nucleophilic addition to form a strategically important C–C bond and afford 66, which was protected as Boc carbamate in the same pot to give 67 in 96% yield from 64. In this tandem sequence, the nucleophilicity

• synthesis, they used an electron-rich and nucleophilic pyrrole as the precursor of the electron-deficient pyridine to enable a tandem sequence involving an intramolecular nucleophilic addition of the pyrrole to an iminium ion to form a key C–C bond. The pyrrole group was then converted to the desired

Recent advances in Norrish–Yang cyclization and dicarbonyl photoredox reactions for natural product synthesis

• Peng-Xi Luo,
• Jin-Xuan Yang,
• Shao-Min Fu and
• Bo Liu

Beilstein J. Org. Chem. 2025, 21, 2315–2333, doi:10.3762/bjoc.21.177

• ; and subsequent conversion of the ketone in 20 to the vinyl iodide in 21 – via hydrazone formation, lithium–halogen exchange, and final nucleophilic substitution – secured the Norrish–Yang cyclization precursor 22. Following systematic optimization of reaction conditions, irradiation of 22 with 100 W

• blue LEDs at room temperature constructed a single diastereoisomer 23 in 90% yield. From 23, the ABCDE pentacyclic skeleton of phainanoids (27) was ultimately established via a Mitsunobu reaction, intramolecular nucleophilic substitution with in situ-generated aryllithium, and protecting group

• (C6F5)3B triggered a Meinwald rearrangement, generating aldehyde 66. Nucleophilic addition, oxidation of the resulting alcohol, and base-promoted epimerization at C6 of 67' delivered 67. Subsequent dihydroxylation of the alkene in 67 and protection of the resulting 1,2-diol as a cyclic carbonate

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

• , initial examples of catalytic methodologies were based on chiral Lewis acid catalysis, with catalysts used in stoichiometric or sub-stoichiometric amounts [38][39]. Porter and Sibi disclosed the first enantioselective examples of conjugate additions to electron-deficient olefins by nucleophilic radicals

• ) [40]. The reactions were catalyzed by chiral Lewis acids and involved conjugate addition of a nucleophilic alkyl radical to an α,β-unsaturated substrate containing an oxazolidinone or pyrrolidinone template. The resulting α-radical was trapped with an allylstannane and the addition and trapping

• excess of radical precursor, (d) use of toxic H-atom sources such as tin hydride, and (e) limited variation in the nature of the radicals (mostly nucleophilic). Organocatalyzed radical reactions Chiral secondary amine-based catalytic systems have been used in several asymmetric transformations [41][42

Pathway economy in cyclization of 1,n-enynes

• Hezhen Han,
• Wenjie Mao,
• Bin Lin,
• Maosheng Cheng,
• Lu Yang and
• Yongxiang Liu

Beilstein J. Org. Chem. 2025, 21, 2260–2282, doi:10.3762/bjoc.21.173

• reaction proceeded via 5-endo-dig cyclization. This pathway involved enol ether attack on the gold-activated alkyne, leading to the formation of oxonium intermediate 2. Subsequently, nucleophilic addition of methanol culminated in the formation of indene motif 5 (Scheme 2, path a). When methanol served

• terminal alkyne proceeded via a gold(I)-catalyzed propargyl-Claisen rearrangement, generating a β-allenic intermediate 35. This intermediate underwent a Markovnikov-type nucleophilic addition followed by a 5-exo-trig cyclization to stereoselectively construct the furo[3,2-b]furan bicyclic framework 36

• nitrogen atom was substituted with strong electron-withdrawing groups, a nucleophilic attack to gold(I)-activated alkyne generated intermediate 38, with subsequent 6-endo-trig cyclization affording benzo[a]carbazole 39 (Scheme 9, path a). Conversely, the activated alkyne was attacked by enol ether to yield

Pd-catalyzed dehydrogenative arylation of arylhydrazines to access non-symmetric azobenzenes, including tetra-ortho derivatives

• Loris Geminiani,
• Kathrin Junge,
• Matthias Beller and
• Jean-François Soulé

Beilstein J. Org. Chem. 2025, 21, 2234–2242, doi:10.3762/bjoc.21.170

• demonstrate that arylhydrazines can serve as practical amine partners in Pd-catalyzed C–N coupling reactions, with regioselectivity toward arylation of the less nucleophilic terminal nitrogen governed by the steric profile of the substrates and the choice of phosphine ligand. These conditions represent a

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

• formed H2 and HO−. The anti-nucleophilic attack of the N atom in A and the following HO− facilitated deprotonation and formed the corresponding 3-iodoindole 11a. Excessive-reduction (a minor side-reaction) of 11a took place as well in certain instances, resulting in the formation of 12a. And for the

• , A proceeded an intramolecular nucleophilic attack by N and deprotonation to finish 15a. The other possible pathway was radical route, in which PhSe• dimerized to reform 14a or added to C≡C bond in 13a to afford B. The subsequent anodic oxidation of B gave C, which underwent nucleophilic cyclization

• phenylselenium cation C and phenylselenium radical B through radical cation species A. Simultaneously, the cathodic reduction of 17a generated anion D and radical B. Then, addition of B with the alkyne portion in 16a gave a radical intermediate E, which proceeded a one-electron oxidation followed by nucleophilic

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

• biomass shows how renewable carbon sources can replace non-renewable chemicals in important industrial processes [18][19][20]. Many, if not most, biobased platform molecules contain carbonyl groups. Carbonyl compounds have unique electrophilic and nucleophilic reactivity which make them central players in

• , arising from a nucleophilic attack of a furan carbon atom of one furfural molecule onto the aldehyde of a second one, giving 2-(4-furfur-2-al)-4-hydroxy-2-cyloepenten-1-one (Scheme 64), resulting from a Piancatelli rearrangement. This latter can further evolve towards more complex humin precursors by