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

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

Synthesis of new tetra- and pentacyclic, methylenedioxy- and ethylenedioxy-substituted derivatives of the dibenzo[c,f][1,2]thiazepine ring system

• Gábor Berecz,
• András Dancsó,
• Mária Tóthné Lauritz,
• Loránd Kiss,
• Gyula Simig and
• Balázs Volk

Beilstein J. Org. Chem. 2025, 21, 2645–2656, doi:10.3762/bjoc.21.205

• substitution reactions of benzo-1,3-dioxoles and benzo-1,4-dioxanes [20]. Reduction of ketones 6 and 7 with NaBH4 gave alcohols 16 and 17, which were chlorinated with SOCl2 to result in compounds 18 and 19. Treatment of the latter with the appropriate amines gave amino derivatives 20a, 20c–e, and 21a, 21c–p

• ): reduction of 8 with NaBH4, followed by chlorination of alcohol 36 with SOCl2 and substitution of chloro derivative 37 with various amines resulted in compounds 38a–c. Tianeptine analogue 38d was obtained by hydrolysis of ester 38c. The synthesis of the new regioisomeric tetracyclic compounds containing the

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

• to replace AcOH by ethanol (Table 1, entry 10), however, the use of ethanol with piperidine was controversial. We found out that, during the reaction with benzaldehyde (1a) and rhodanine (2a), a multicomponent reaction was taking place by a substitution process, leading directly to 2-amino-5

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

Palladium-catalyzed regioselective C1-selective nitration of carbazoles

• Vikash Kumar,
• Jyothis Dharaniyedath,
• Aiswarya T P,
• Sk Ariyan,
• Chitrothu Venkatesh and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2025, 21, 2479–2488, doi:10.3762/bjoc.21.190

• and functional materials (Scheme 1a) [62][63][64][65][66]. Traditional electrophilic aromatic substitution methods for the nitration of carbazole typically result in a mixture of 1-nitro-, 2-nitro-, and 3-nitro-substituted isomers (Scheme 1b) [67]. Therefore, developing a method for the regioselective

• less hindered site. Halogenated substrates 1q and 1r (3-Cl and 3-Br substitution) delivered products 2q (37%) and 2r (31%) in moderate yield. Notably, the reaction of 1r also furnished 2a (9%), indicating competitive debromination. Finally, benzocarbazole substrate 1s afforded a mixture of regioisomers

• ). Plausible catalytic cycle. (a) Representative examples of bioactive nitrocarbazoles. (b) Traditional electrophilic aromatic substitution approach for the nitration of carbazole. (c) Present work: palladium-catalyzed directed C1-selective nitration reaction. Effect of directing groups on the nitration of the

Ex-situ generation of gaseous nitriles in two-chamber glassware for facile haloacetimidate synthesis

• Nikolai B. Akselvoll,
• Jonas T. Larsen and
• Christian M. Pedersen

Beilstein J. Org. Chem. 2025, 21, 2465–2469, doi:10.3762/bjoc.21.188

• substitution patterns. We began with carbohydrates, as the products are analogs of the trichloroacetimidates, which constitute the most commonly used class of glycosyl donors for glycoside synthesis [23]. Their trifluoro-analogs have, however, only been scarcely studied due to the difficulties in handling 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

• efficiently constructed by catalytic asymmetric hydroselenation, catalytic asymmetric allyl substitution, catalytic asymmetric electrophilic selenylation/cyclization, etc. The research content of this part has already been covered by relevant reviews [15][16][17], so it is not within the scope of discussion

• 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

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

• + macrocycle and promotes its translation away from the acridane toward the secondary site. However, if the rotaxane contains only one recognition site, the macrocycle remains at the unfavorable acridinium station, interacting with the 9-aryl group. Therefore, substitution at this position was employed to tune

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

Insoluble methylene-bridged glycoluril dimers as sequestrants for dyes

• Suvenika Perera,
• Peter Y. Zavalij and
• Lyle Isaacs

Beilstein J. Org. Chem. 2025, 21, 2302–2314, doi:10.3762/bjoc.21.176

• -surfaces and which are activated for electrophilic aromatic substitution reactions. For the synthesis of W1, we initially prepared tetramethoxybiphenyl 1 (Scheme 1) according to the literature procedure involving the Suzuki coupling between 3,4-dimethoxybromobenzene and 3,4-dimethoxyphenylboronic acid [44

• discern the effect of smaller aromatic sidewalls. The synthesis of acyclic CB[n]-type receptors follows a building block approach involving the reaction of a glycoluril bis(cyclic) ether with an activated aromatic wall by a double electrophilic aromatic substitution process [30]. Scheme 2 shows the

Halogenated butyrolactones from the biomass-derived synthon levoglucosenone

• Johannes Puschnig,
• Martyn Jevric and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2025, 21, 2297–2301, doi:10.3762/bjoc.21.175

• envisaged that halogenation could be combined with the Baeyer–Villiger oxidation which yields the butyrolactones by excision of C5, a reaction which is tolerant to substitution at C3 and can be carried out on a kilogram scale [30]. The present work was focussed on the development of additional halogenation

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

• one way to convert a free radical to a more stable intermediate, which can subsequently undergo coupling with another radical via an SH2 (bimolecular homolytic substitution) mechanism. Lastly, some noteworthy radical processes proceed through a radical–polar crossover pathway, in which one-electron

• diazoester 24 to furnish a Co(III)-bonded α-ester radical (α-Co(III)-ester radical) with extrusion of nitrogen was proposed by the authors. Further steps include (a) 5-exo cyclization by α-Co(III)-ester radical and (b) homolytic substitution at the carbon atom by 3-exo-tet-cyclization to generate bicyclic

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

• synthetic value of this method. In 2017, the Liu group established a precise control over cyclization sequences of 1,2-diphenylacetylenes by modulating the nitrogen-substitution patterns, enabling divergent syntheses of benzo[a]carbazole and indeno[1,2-c]quinoline derivatives (Scheme 9) [16]. When the

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

• optimize the reaction conditions, with particular focus on the choice of ligand, especially for non-ortho-substituted aryl bromides as substrates. Notably, the use of bulkier phosphines, such as P(t-Bu)3 and t-BuXPhos, was found to promote the reaction regardless of the substitution pattern of the

• valuable addition to existing methodologies and open further opportunities for applications in molecular probe design, functional materials, and photoresponsive systems, where ortho-substitution is often critical. General overview of azobenzene chemistry. a) Selected examples and photoisomerization of

Thiadiazino-indole, thiadiazino-carbazole and benzothiadiazino-carbazole dioxides: synthesis, physicochemical and early ADME characterization of representatives of new tri-, tetra- and pentacyclic ring systems and their intermediates

• Gyöngyvér Pusztai,
• László Poszávácz,
• Anna Vincze,
• András Marton,
• Ahmed Qasim Abdulhussein,
• Judit Halász,
• András Dancsó,
• Gyula Simig,
• György Tibor Balogh and
• Balázs Volk

Beilstein J. Org. Chem. 2025, 21, 2220–2233, doi:10.3762/bjoc.21.169

• 7c compared to 7b is likely due to the structural differences, with 7a and 7c having asymmetric substitutions (methyl for 7c, R2 = H, R3 = Me and ethyl, methyl for 7a, R2 = Me, R3 = Me), while 7b having a symmetric diethyl substitution pattern (R2 = Et, R3 = Me). The comparison of the solubility of

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

• reversible C–H activation to give the six-membered intermediate C. Substitution of the acetate ligand in C by 3 caused the generation of complex D. The six-membered ruthenacycle E was then obtained by migratory insertion of acetylene into the Ru–C bond. Finally, reductive elimination of E formed the target

• nucleophilic substitution of D afforded target indeno[1,2-c]pyrrole 40a along with eliminating I. Notably, this oxidant-free and catalyst-free approach could be potentially applied in the pharmaceutical manufacture. A Rh-promoted synthesis of pyrroles through annulation of alkynes and enamides was demonstrated