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

• efficacy [2]. Activation of the 5-HT2AR is thought to induce altered states of consciousness and suppress the default-mode network, a process hypothesized to underlie their clinical benefits [3]. However, classic psychedelics lack receptor selectivity, prompting efforts to develop more selective 5-HT2AR

• selective 5-HT2AR activation in vitro and in vivo [6]. A review published in 2021 provide an in-depth introduction to the pharmacological properties and various applications [7]. More recent examples include the mapping of the cortical correlates of the so-called head-twitch response in mice [8

• . Taken together, this investigation further supports the use of 25CN-NBOH (1) for investigations into the effects of selective 5-HT2AR activation. Our data provides guidance to researchers for the handling and physiochemical properties of the compound when considering its use in various research

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

• previously disclosed a PIDA-mediated oxidative strategy for alcohol incorporation via activation of the S–NH bond (Scheme 1a) [14]. More recently, Wu and co-workers advanced the field by developing a dynamic kinetic resolution protocol for the enantioselective synthesis of sulfinimidate esters from racemic

• limitations, we envisioned that highly electrophilic sulfilimidoyl intermediates – generated in situ via N-halosuccinimide-mediated oxidative activation of sulfenamides – could be directly intercepted by alcohols under basic conditions to furnish structurally diverse sulfinimidate esters [32]. In particular

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

• widely used to achieve these valuable compounds [10][11][12]. Enamine activation was one of the first organocatalytic methods applied in Mannich reactions [13][14]. Concurrently, hydrogen-bond catalysis has emerged as a significant strategy for promoting asymmetric Mannich reactions [15][16]. This has

• efficient in Mannich reactions, as demonstrated by our studies [18] and those of others [19][20][21]. Halogen bonding has also been introduced to further broaden the field of noncovalent interactions. Despite the limited number of asymmetric transformations driven solely by halogen-bond activation [22

• reactions to imines [27]. The model reaction was performed in the presence of various types of catalysts (Figure 1). The syntheses of the catalysts are described in Supporting Information File 1. All catalysts used are amides containing tertiary amino groups, which are needed for the activation 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

• limitation requires the design of catalysts that achieve precise electronic complementarity, enabling selective activation across a broad spectrum of aromatic compounds (Scheme 2) [32]. From the standpoint of scalable synthesis, catalyst cost is a major bottleneck in aromatic hydrogenation. Most state-of-the

• heterocycles exhibit strong Lewis basicity, potentially complexing and deactivating catalysts. Consequently, the catalytic hydrogenation of six-membered aromatic heterocycles such as pyridine often requires the introduction of substituents or activation of the aromatic heterocycle to facilitate hydrogenation

Advances in Zr-mediated radical transformations and applications to total synthesis

• Hiroshige Ogawa and
• Hugh Nakamura

Beilstein J. Org. Chem. 2026, 22, 71–87, doi:10.3762/bjoc.22.3

• iodide 10n failed to give the desired products. In substrate 10o containing both iodide and bromide, selective activation of the alkyl iodide was observed, affording the coupled product in 96% yield. Furthermore, the reaction proceeded smoothly in the presence of alcohols 10p–q and carboxylic acid 10r

• potential and stabilizing the radical pathway. The DFT calculations are shown in Scheme 13A. The activation barrier for the XAT process was calculated to be ΔG‡ = 8.0 kcal/mol, indicating that this process can proceed spontaneously around room temperature. Moreover, the transition state (TS1) suggested the

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

• stereoselectivity, exclusively yielding the Z-isomer. Nonan-2-one required activation with the stronger methanesulfonic acid and gave a 91:9 regioisomeric mixture of 91 to 92. 1-Tetralone provided the corresponding product 61 in only 7% yield; the acid additive was not specified in this case. The authors were

• initiated by the activation of allyl bromide using InCl3 (Scheme 48C) [158]. Very likely the first step involves the generation of allyl cation I by activation of the allyl bromide with InCl3. Subsequent trapping by the appended alkyne will form alkenyl cation II. Cation II then reacts with dichloromethane

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

• of 0.1 V/s at 298 K. Free energy diagram of possible interaction pathways between 1a and dinitramide-derived radical A according to ωB97X-3c [94]/CPCM(MeCN) level of theory. Free energies ΔG and activation free energies ΔG≠ are given in kcal/mol. Dashed lines correspond to spin-state-changing

• -azoxylation of nitrosoalkanes containing electron-withdrawing groups. Synthetic utility and derivatization of synthesized coupling product 2f. Control experiments. Proposed mechanism for electrochemical nitro-NNO-azoxylation of 1-nitro-1-nitroso compounds 1. Free energies ΔG and activation free energies ΔG

Total synthesis of asperdinones B, C, D, E and terezine D

• Ravi Devarajappa and
• Stephen Hanessian

Beilstein J. Org. Chem. 2025, 21, 2730–2738, doi:10.3762/bjoc.21.210

• gene clusters that code for a (3R) configuration. Keywords: C–H activation; indole alkaloid; Negishi reaction; prenylation; Introduction Alkaloids constitute an important family of naturally occurring compounds with a rich history in the annals of bioactive compounds [1]. Among these, the family of

• alternative approach to C-7 functionalization of Nα-Boc-tryptophan methyl ester, we chose a CH activation protocol [33]. Treatment of N1-Piv-Nα-Boc-tryptophan methyl ester (10) with but-3-en-2-one (MVK) in the presence of [RhCp*Cl2]2 catalyst according to Ma et al. [34] led to the 7-(3-keto-1-butyl)-alkylated

• , the Pirrung group reported two practical syntheses of 7-prenylindole [48][49]. The regioselective C-7 prenylation of indole has been achieved by directing-group C–H activation as reported by Snieckus [50]. However, the deprotection of the preferred N-bis-tert-butylphosphinoyl directing group required

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

• and Figure 3. For chalcones with X = –Cl, –NO2 the activation Gibbs free energies for step Int3 → T.S. → vicinal product (Scheme 4) for the formation of the α,β-ditosyloxy ketones are 12.88 kcal/mol, 13.22 kcal/mol, respectively, while for the formation of the β,β-ditosyloxy ketones, the corresponding

• same is not true when X is an electron-donating group. For X = -OCH3, -SCH3 activation Gibbs free energies for step Int3 → T.S. → vicinal product (Scheme 4) leading to formation of α,β-ditosyloxy ketones are 14.40 kcal/mol, 16.01 kcal/mol, respectively, while in case of the formation of β,β-ditosyloxy

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

• 3-position, a copper-mediated C–H activation of position 12 and subsequent protection of the introduced hydroxy moiety to give compound 25 (Scheme 6). Installation of the lactone moiety in 22 was carried out in a three-step sequence via a 1,2-addition of organocerium reagent 26 to the ketone

• , with the hydroxy group at C17 playing a crucial role trapping a cationic intermediate from this rearrangement. Starting point in this synthesis is again dehydroepiandrosterone (24), which was protected in 3-position with an acetyl group (Scheme 12). A copper-mediated C–H activation procedure to obtain

• the semisynthesis of Liu/Qin [26] 15 years later. The only non-green transformations displayed at the start were a protecting group installation (red) and a condensation (yellow), which was needed for the C–H activation (light green). All other transformations connect either C–C or C–heteroatom bonds

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

• ]. The use of visible light as an energy source has significantly expanded the scope of organic molecule activation and its application in organic synthesis or medicinal chemistry [12], thereby driving the fast development of various photocatalytic transformations. Among these advances, dual catalysis

• process, such as being environmentally friendly, offering operational simplicity, lower cost, and easy availability, reducing waste and toxicity, as well as providing excellent chemo-, regio-, and enantioselectivity through fine-tuned hydrogen bonding or covalent activation modes. Furthermore, the

• silylboronates 13. This photochemical method operates via catalytic activation of the silylboronate 13 in the presence of NHC (10 mol %) and 4CZIPN (1 mol %) with Rb2CO3 (10 mol %) as a base in CH3CN at rt for 20 h. The approach affords highly functionalized β-silylated aryl ketones 14 in moderate to good yields

Total syntheses of highly oxidative Ryania diterpenoids facilitated by innovations in synthetic strategies

• Zhi-Qi Cao,
• Jin-Bao Qiao and
• Yu-Ming Zhao

Beilstein J. Org. Chem. 2025, 21, 2553–2570, doi:10.3762/bjoc.21.198

• , provided carboxylic acid 113 in a single operation. Subsequent activation of 113 with acetic anhydride, relactonization, and organoselenium-mediated regioselective epoxide opening yielded mono-enone 114, successfully installing the key C9 and C10 chiral centers with the required oxidation states. Notably

Effect of a photoswitchable rotaxane on membrane permeabilization across lipid compositions

• Udyogi N. K. Conthagamage,
• Lilia Lopez,
• Zuliah A. Abdulsalam and
• Víctor García-López

Beilstein J. Org. Chem. 2025, 21, 2498–2512, doi:10.3762/bjoc.21.192

• photochemical process occurs, which triggers the release from only the vesicles containing EYPC. These findings underscore the significance of both the physical and chemical properties of the bilayer in enabling effective light-triggered cargo release through rotaxane activation. Keywords: lipid membrane

• bacteria or malignant cells like cancer) [5][6], or to influence membrane protein function and thereby control cellular behavior [7][8]. One promising approach is the development of light-activated molecules that can modulate membrane properties upon irradiation, enabling remote activation with high

• light activation of axle 3. Lastly, in LUVs composed of DPPC, irradiation of rotaxane 1 resulted in a total sulforhodamine B release of 14%, representing an increase compared to the minimal release observed under non-irradiated conditions (3–7%) (Table 1 and Figure 6). In contrast, irradiation of

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

• valuable platform for the selective functionalization of carbazoles, offering potential applications in optoelectronics, functional organic materials, and related areas while contributing to the advancement of C–H activation methodologies. Keywords: C–H activation; carbazole; catalysis; nitration

• addition to cross-coupling reactions, transition metal-catalyzed cyclization involving C–H activation approaches have also been reported [29][30][31][32][33][34][35][36]. Despite the significant advances in carbazole core constructions, the established protocols significantly lack access to selectively C1

• -decorated carbazoles. Consequently, functionalizing carbazoles via transition metal-catalyzed directed C–H activation becomes more attractive to introduce the desired functionality in a regioselective fashion. The C–H activation strategy is elegant in many ways since it utilizes nonfunctionalized or lesser

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

• the N atom is positioned antiperiplanar to the adjacent C19–C3 bond, an intermediate IN4 with a bicyclo[2.2.0]hexane unit was successfully located. However, the Gibbs free energy of IN4 (ΔG° = +27.4 kcal/mol) is significantly higher than the activation energy of TS2 (ΔG‡ = 22.4 kcal/mol). This energy

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

• axially chiral selenium-containing compounds by the formation of C–Se bonds is reviewed from three aspects. Review 1. Catalytic atroposelective synthesis of selenium-containing atropisomers by transition-metal-catalyzed C–H selenylation reactions Transition-metal-catalyzed enantioselective C–H activation

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

• ring contraction reaction on simple cyclohexanones to synthesize functionalized di- and triquinanes [51]. Treatment of 6-oxabicyclo[3.2.1]octan-8-one 86 with BF3·Et2O (2 equiv) promoted the activation of the carbonyl group in 87 by the Lewis acid, leading to the formation of an oxocarbenium ion 88

Synthetic study toward vibralactone

• Liang Shi,
• Jiayi Song,
• Yiqing Li,
• Jia-Chen Li,
• Shuqi Li,
• Li Ren,
• Zhi-Yun Liu and
• Hong-Dong Hao

Beilstein J. Org. Chem. 2025, 21, 2376–2382, doi:10.3762/bjoc.21.182

• this key intermediate in hand, β-hydroxy acid 29 was synthesized through deprotection, IBX oxidation, and Pinnick–Lindgren–Kraus oxidation and the β-lactone 13 was subsequently obtained through activation of the carboxylic acid. Although we successfully constructed the molecular scaffold of

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

• the macrocycle interaction with the axle. In a different approach, the authors demonstrated that the macrocycle can shuttle along an axle by incorporating two acridane photoswitches at both ends. However, upon light activation, the macrocycle stops shuttling and remains in the middle of the axle

• authors successfully prepared the corresponding pseudorotaxane (lacking stopper groups), which underwent dethreading upon light activation, demonstrating the potential of acridane-based macrocycles for light-controlled mechanical motion in rotaxanes. Anthracene Hirose and co-workers developed [2]rotaxanes

• surrounding environment. Controlling macrocycle shuttling via light activation has proven valuable for enabling secondary functions. For example, when integrated into polymers or gels, the mechanical motion of rotaxanes can be harnessed to control the macroscopic properties of materials or even generate

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

• catalysis, C–H activation methods, biomimetic synthesis, classic rearrangements, skeletal editing logic, and others. In addition, these efforts enabled the identification of the potential cellular target of complanadine A, validation of its neurotrophic activity, establishment of preliminary structure

• ] cycloadditions. The Sarpong total synthesis of complanadine A enabled by a biomimetic strategy and C–H activation. The Tsukano total synthesis of complanadine A enabled by Diels–Alder cycloaddition, Heck cyclization, and directed C–H arylation. The Dai total synthesis of complanadine A using single-atom skeletal

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

• favor Norrish–Yang cyclization over the competing unproductive Norrish type II fragmentation pathway; (2) the long excitation wavelength of 1,2-diketones (λmax ≈ 450 nm) enables their selective activation in the presence of other photochemically excitable groups [5][6]. Furthermore, the resulting α

• –Yang cyclization and related photoredox reactions, owing to their ability to undergo selective activation under mild conditions (e.g., long-wavelength irradiation) – a feature that minimizes competing fragmentation pathways. Notably, different dicarbonyl substrates exhibit distinct reactivity patterns

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

• ]. MacMillan obtained chiral free radicals by stoichiometric single electron transfer (SET) oxidation of enamines, formed by the reaction between chiral secondary amines and aldehydes. This mode of activation was called SOMO (singly occupied molecular orbital) catalysis and was employed in several organic

• substrates or organometallic complexes upon photoexcitation has enabled the synthetic community to access reactive open-shell species under very mild conditions. The ability of excited photocatalysts to induce other reagents, substrates, or other catalysts to participate in new activation modes makes them a

• , particularly involving photoredox catalysts, have led to the emerging area of photoenzymatic catalysis. Several new modes of activation successfully catalyzed by enzymes have been demonstrated [71][72][73][74]. Notable photoenzymatic reactions involving radical cyclizations have been reported. In one

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

• regulatory role in chemical transformations, exerting kinetic modulation through solvation effects on activation barriers and reaction rates, dictating thermodynamic equilibria that govern product distribution, and enabling precise reaction pathway regulation via selective stabilization of critical

• dichloromethane (DCM), gold(I)-catalyzed alkyne activation initiated 6-endo-dig cyclization of the conjugated alkene. Subsequent alkyl migration formed four-membered ring intermediate 9, which underwent fragmentation and rearrangement to yield phenanthrene derivative 10 (Scheme 3, path a). When tetrahydrofuran

• cyclization and subsequent deprotonation furnished 1,3-disubstituted or 1,2,3-trisubstituted naphthalenes 29 (Scheme 7, path a). When the alkyne terminus was iodo-substituted or unsubstituted, the 5-exo-dig cyclization pathway proceeded via selective activation of the iodoalkyne, generating 1-methyleneindene

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

• for 6 h. The authors also proposed the reaction mechanism on basis of experimental results and previous literature [205][206]. Firstly, the ligand exchange between (R)-Rh1 and n-Bu4NOAc or 1-AdCO2H gave a chiral active catalyst A. The irreversible base-prompted C–H activation of A with 19a yielded a

• of 22 with Cu(OPiv)2 and the following anodic copper(II) oxidation provided copper(III) carboxylate intermediate B. Facile carboxylate-promoted C–H activation and ligand exchange with 23 formed the copper(III) species D, which underwent metalation/reductive elimination to generate intermediate E

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

• valuable chemical used in the feed and food industry, is produced by petrochemical processes. Its synthesis from biobased lactic acid (LA) offers an access from renewable resources. However, this conversion is difficult due to the high activation energy required for the hydrogenation reaction removing the

• toward useful biobased functional compounds or intermediates with applications in fuels, polymer chemistry and fine organic synthesis (CH activation, Piancatelli rearrangement, etc.). Conversion of furfural to alcohols, aldehydes and ketones: One of the most important transformations of furfural is its