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

Discovery of cytotoxic indolo[1,2-c]quinazoline derivatives through scaffold-based design

• Daniil V. Khabarov,
• Valeria A. Litvinova,
• Lyubov G. Dezhenkova,
• Dmitry N. Kaluzhny,
• Alexander S. Tikhomirov and
• Andrey E. Shchekotikhin

Beilstein J. Org. Chem. 2025, 21, 2062–2071, doi:10.3762/bjoc.21.161

• )-one scaffold 1 was synthesized according to the optimized protocol developed by Bergman et al. [9]. Position 12 of indolo[1,2-c]quinazolin-6(5H)-one (1) (Scheme 1) corresponded to of the indole C3 position, which is typically used as a nucleophilic center for functionalization via reactions with

• position 12 [23]. The most straightforward synthetic strategy for formation of an carboxamide group at position 12 of the indolo[1,2-c]quinazolin-6(5H)-one (1) scaffold involved a two-step sequence: (1) carboxylation of the nucleophilic C12 position, followed by coupling with appropriate amines. To

• NH proton in the urea moiety (position N5) of indolo[1,2-c]quinazolin-6(5H)-one (1) enables efficient N-alkylation. Accordingly, alkylation of 1 with 1-bromo-3-chloropropane afforded intermediate 11, bearing a reactive chloropropyl side chain suitable for further derivatization. Nucleophilic

Bioinspired total syntheses of natural products: a personal adventure

• Zhengyi Qin,
• Yuting Yang,
• Nuran Yan,
• Xinyu Liang,
• Zhiyu Zhang,
• Yaxuan Duan,
• Huilin Li and
• Xuegong She

Beilstein J. Org. Chem. 2025, 21, 2048–2061, doi:10.3762/bjoc.21.160

• , Wittig reaction with MOMPPh3Cl and LDA gave the putative methyl enol ether, which could be directly converted into 1,3-dithiane 12 with propane-1,3-dithiol. Nucleophilic addition to chiral epoxide 13 and oxidative hydrolysis of 1,3-dithiane to ketone delivered chiral β-hydroxyketone 14. Evans−Tishchenko

• analysis. The major one 48b was used for further study to install the pyrrolidine system. Thus, nucleophilic addition of an N,O-enolate, derived from precursor 49 with LDA, to the ketone functionality in 48b was implemented to generate a pair of inseparable regioisomers 50a and 50b, arose from C4 and C7

Measuring the stereogenic remoteness in non-central chirality: a stereocontrol connectivity index for asymmetric reactions

• Ivan Keng Wee On,
• Yu Kun Choo,
• Sambhav Baid and
• Ye Zhu

Beilstein J. Org. Chem. 2025, 21, 1995–2006, doi:10.3762/bjoc.21.155

• coupling of biaryls is designated as [30 20]. In addition to biaryls, axially chiral allenes are popular targets for asymmetric synthesis. Three examples of asymmetric reactions that form axially chiral allenes are shown in Scheme 4. For example, the enantioselective nucleophilic substitution to yield

Aryl iodane-induced cascade arylation–1,2-silyl shift–heterocyclization of propargylsilanes under copper catalysis

• Rasma Kroņkalne,
• Rūdolfs Beļaunieks,
• Armands Sebris,
• Anatoly Mishnev and
• Māris Turks

Beilstein J. Org. Chem. 2025, 21, 1984–1994, doi:10.3762/bjoc.21.154

• alkynes undergo 1,2-carbofunctionalization, where the highly electrophilic Ar–M species adds to the alkyne, generating a vinyl cation intermediate [7], which typically reacts with an internal nucleophile to form five- [8][9] or six-membered rings [7][9][10] (Scheme 1A). Thus far the internal nucleophilic

• -catalyzed propargylsilane activation pathway [26]. Therefore, the presence of a base was imperative. The only applicable base was found to be the non-nucleophilic 2,6-di-tert-butylpyridine (B1, Table 1, entries 1–6, 9–18). We also considered the structurally similar, but less sterically hindered 2,6

• standard column chromatography techniques (30–50% DCM). Iodanes, containing electron-rich aryl groups (p-Tol, m-MeO-C6H4, Ph) or halogens (Br, F) gave the highest tetrahydrofuran 8 yields (70–83%). In contrast, electron-withdrawing group-containing iodanes, especially those holding nucleophilic heteroatoms

Photochemical reduction of acylimidazolium salts

• Michael Jakob,
• Nick Bechler,
• Hassan Abdelwahab,
• Fabian Weber,
• Janos Wasternack,
• Leonardo Kleebauer,
• Jan P. Götze and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2025, 21, 1973–1983, doi:10.3762/bjoc.21.153

• intermediate A (Figure 1a), in which the formerly electrophilic carbonyl carbon reacts as a nucleophilic center. In this way, the traditional reactivity profile of the carbonyl group is transiently inverted, and unconventional product classes are generated. Alternatively, addition/elimination of the NHC to a

Enantioselective desymmetrization strategy of prochiral 1,3-diols in natural product synthesis

• Lihua Wei,
• Rui Yang,
• Zhifeng Shi and
• Zhiqiang Ma

Beilstein J. Org. Chem. 2025, 21, 1932–1963, doi:10.3762/bjoc.21.151

• benzylic C11 position of 268 was first oxidized to generate intermediate 269, followed by intramolecular nucleophilic attack of the hydroxy group. This stereoselective cyclization constructed the tetrahydropyran ring of pentacyclic compound 270 in 92% yield and established the stereocenter at the C7

• , wherein one hydroxy group underwent nucleophilic attack on the C2 electrophilic center while the other remained unreacted, giving furoindoline 284 in 45% yield. A final two-step transformation completed the synthesis of (−)-ψ-akuammigine (285). In 2021, the Ding group reported the total synthesis of two

Rhodium-catalysed connective synthesis of diverse reactive probes bearing S(VI) electrophilic warheads

• Scott Rice,
• Julian Chesti,
• William R. T. Mosedale,
• Megan H. Wright,
• Stephen P. Marsden,
• Terry K. Smith and
• Adam Nelson

Beilstein J. Org. Chem. 2025, 21, 1924–1931, doi:10.3762/bjoc.21.150

• ][3]. Established sets of reactive probes are typically armed with electrophilic warheads that have the potential to target nucleophilic amino acid side chains. Most reactive probe sets bear cysteine-directed warheads [3][4][5][6][7], although sets have also been designed to target a wider range of

Synthesis, biological and electrochemical evaluation of glycidyl esters of phosphorus acids as potential anticancer drugs

• Almaz A. Zagidullin,
• Emil R. Bulatov,
• Mikhail N. Khrizanforov,
• Damir R. Davletshin,
• Elvina M. Gilyazova,
• Ivan A. Strelkov and
• Vasily A. Miluykov

Beilstein J. Org. Chem. 2025, 21, 1909–1916, doi:10.3762/bjoc.21.148

• . When these agents alkylate the HSA amino acid residues (particularly reactive sites like lysine, cysteine, serine NH2, SH, OH-side chains, and possibly other nucleophilic groups), the resulting covalent modification can disrupt the electroactive centers responsible for the protein’s oxidation peaks

• , the significant suppression or disappearance of the HSA oxidation peak upon addition of glycidyl esters 1–3 can be interpreted as evidence of covalent modification (alkylating) of nucleophilic sites on HSA, rather than non-specific binding or merely non-reactive association [27][28][29]. The observed

• compounds 1–3 strongly indicates their ability to covalently modify nucleophilic sites in proteins. This finding underscores the potential of LSV as a rapid and effective tool for assessing alkylating reactivity, with implications for future drug development. Overall, this study offers meaningful insights

Photoswitches beyond azobenzene: a beginner’s guide

• Michela Marcon,
• Christoph Haag and
• Burkhard König

Beilstein J. Org. Chem. 2025, 21, 1808–1853, doi:10.3762/bjoc.21.143

• (37) followed by reduction with Zn/Ba(OH)2 and partial re-oxidation (Scheme 12A) [52]. They can also be obtained from o-halogenated benzyl bromides 40 by lithium–halogen exchange followed by nucleophilic substitution and a second lithium–halogen exchange with iodine (Scheme 12B) or by nickel-catalysed

• aldehyde and, if required, N-functionalisation via nucleophilic substitution (for aliphatic substituents) or palladium-catalysed cross-coupling (for aromatic substituents) (Scheme 25) [77]. Hemithioindigo can be synthesised by treating phenylthioacetic acid (83) with triflic acid. Then, the product is

Synthesis of chiral cyclohexane-linked bisimidazolines

• Changmeng Xi,
• Qingshan Sun and
• Jiaxi Xu

Beilstein J. Org. Chem. 2025, 21, 1786–1790, doi:10.3762/bjoc.21.140

• nucleophilically attacks the phosphonium in A to generate intermediate B by loss of triphenylphosphine oxide and triflic acid. The nucleophilic sulfonamide in B intramolecularily attacks the generated imine moiety in B to form intermediate C, in which triflic acid may protonate the imine moiety in B to assist the

• nucleophilic attack. Intermediate C further transforms to imidazoline product 5 by loss of triphenylphosphine oxide and triflic acid. Conclusion Both chiral bisoxazolines and bisimidazolines are efficient and widely applied chiral ligands in metal-catalyzed asymmetric organic reactions. Several chiral

3,3'-Linked BINOL macrocycles: optimized synthesis of crown ethers featuring one or two BINOL units

• Somayyeh Kheirjou,
• Jan Riebe,
• Maike Thiele,
• Christoph Wölper and
• Jochen Niemeyer

Beilstein J. Org. Chem. 2025, 21, 1719–1729, doi:10.3762/bjoc.21.134

• ]. For the synthesis of macrocycles M2 with two BINOL units, we relied on the monoiodide 12, which was first reacted in a two-fold Suzuki coupling to install the first linker, followed by silyl deprotection and introduction of the second linker via nucleophilic substitution [51]. Both procedures require

Approaches to stereoselective 1,1'-glycosylation

• Daniele Zucchetta and
• Alla Zamyatina

Beilstein J. Org. Chem. 2025, 21, 1700–1718, doi:10.3762/bjoc.21.133

• substituents, thereby minimizing the likelihood of oxocarbenium ion formation from the silyl aldoside acceptors 50 and 53 (Scheme 5). Nucleophilic attack by 1-O-trimethylsilyl β-pyranosides 50 or 53 on the α-face of the oxocarbenium ions afforded the corresponding β-ketopranosyl α-aldopyranosides 51 and 54

Influence of the cation in hypophosphite-mediated catalyst-free reductive amination

• Natalia Lebedeva,
• Fedor Kliuev,
• Olesya Zvereva,
• Klim Biriukov,
• Evgeniya Podyacheva,
• Maria Godovikova,
• Oleg I. Afanasyev and
• Denis Chusov

Beilstein J. Org. Chem. 2025, 21, 1661–1670, doi:10.3762/bjoc.21.130

• the DFT calculations (Scheme 5, Figure 2). Firstly, reductive amination of an aldehyde started from a nucleophilic addition of the amine to the carbonyl group of the aldehyde. In the presence of acid, this step could occur via acidic catalysis involving a protonation step of an amine (Step_2) or

• weakly nucleophilic secondary ammonium cation to the carbonyl group occurred with ΔEa = 11.5 kcal/mol (TS2→3). In recent DFT [39] and experimental [40] studies on the reductive amination reaction it was postulated that this protonation of amine played a key role in the catalytic cycle especially in the

Catalytic asymmetric reactions of isocyanides for constructing non-central chirality

• Jia-Yu Liao

Beilstein J. Org. Chem. 2025, 21, 1648–1660, doi:10.3762/bjoc.21.129

• condensation between 27 and the aldehyde afforded INT-A, which was activated by the CPA catalyst through hydrogen bonding interaction. The nucleophilic addition of isocyanide to Int-A produced INT-B bearing a stereogenic center. Subsequently, INT-B underwent intramolecular cyclization to generate axially

Photocatalysis and photochemistry in organic synthesis

• Timothy Noël and
• Bartholomäus Pieber

Beilstein J. Org. Chem. 2025, 21, 1645–1647, doi:10.3762/bjoc.21.128

• of alkenylboronic esters using energy transfer catalysis [26]. Gualandi and co-workers leveraged a combination of photoredox and HAT catalysis to realize the intramolecular nucleophilic amidation of alkenes with β-lactams [27]. Further, Luridiana and colleagues developed a method for the alkylation

Formal synthesis of a selective estrogen receptor modulator with tetrahydrofluorenone structure using [3 + 2 + 1] cycloaddition of yne-vinylcyclopropanes and CO

• Jing Zhang,
• Guanyu Zhang,
• Hongxi Bai and
• Zhi-Xiang Yu

Beilstein J. Org. Chem. 2025, 21, 1639–1644, doi:10.3762/bjoc.21.127

• introduce an ester group at the α position of the carbonyl group in 9 to get compound 10, which could have a more nucleophilic carbon better for the Heck reaction. 10 was obtained in 70% yield with a diastereomeric ratio of 4.5:1. Then, we screened various palladium catalysts and solvents to accomplish the

3-Aryl-2H-azirines as annulation reagents in the Ni(II)-catalyzed synthesis of 1H-benzo[4,5]thieno[3,2-b]pyrroles

• Julia I. Pavlenko,
• Pavel A. Sakharov,
• Anastasiya V. Agafonova,
• Derenik A. Isadzhanyan,
• Alexander F. Khlebnikov and
• Mikhail S. Novikov

Beilstein J. Org. Chem. 2025, 21, 1595–1602, doi:10.3762/bjoc.21.123

• -containing compounds [1][2][3]. Such reactions can be initiated by electrophilic, nucleophilic or radical reagents, photoirradiation or proceed under acid-, metal-, or photocatalytic conditions. This strategy of azirine ring expansion is applicable to the synthesis of a variety of 4‒9-membered N-heterocycles

• an ortho-substituent into the benzene ring also has no effect on the synthesis efficiency (compound 3f). A slight decrease in yield was observed only for the naphthyl-substituted annulation product 3k. The plausible mechanism of the reaction involves the nucleophilic addition of the Ni-enolate of 1

• diastereomer and characterized by NMR and HRMS data. Compound 13 is likely formed from aziridine 14 via the N→N acetyl group transfer and subsequent isomerization of the acetylaziridinyl substituent. The constitutional isomer of indole 9a, indole 15, having a nucleophilic reaction center in the β-position of

General method for the synthesis of enaminones via photocatalysis

• Paula Pérez-Ramos,
• Raquel G. Soengas and
• Humberto Rodríguez-Solla

Beilstein J. Org. Chem. 2025, 21, 1535–1543, doi:10.3762/bjoc.21.116

• indicate that the key to the success of this process is the formation of an unexplored ternary Ni-complex with 3-bromochromone and a pyridinium salt, which is crucial for the effective activation of the α,β-unsaturated system towards the nucleophilic addition. Keywords: chromones; dehalogenation

• enaminones. This transformation is simple, straightforward, and proceeds under mild conditions. Results and Discussion The initial challenge in achieving the desired reactivity was the activation of the unsaturated system towards the nucleophilic addition of the amine. The most common strategy to increase

• mechanism for this reaction is proposed in Scheme 5. A ternary complex is initially formed upon complexation of 3-bromochromone (7a) with NiBr2-dmbpy. By virtue of being coordinated to a Ni-center, the β-carbon is activated toward nucleophilic attack of the amine, furnishing 2-amino-3-bromochromenone I

Calcium waste as a catalyst in the transesterification for demanding esters: scalability perspective

• Anton N. Potorochenko and
• Konstantin S. Rodygin

Beilstein J. Org. Chem. 2025, 21, 1520–1527, doi:10.3762/bjoc.21.114

• , under these conditions, the inertness of alcohols 2j and 2k in the transesterification of both soybean oil and esters with less-hindered structures was probably due to their poor nucleophilic properties. The CS600 catalyst was investigated in the transesterification of low-molecular-weight esters

Ambident reactivity of enolizable 5-mercapto-1H-tetrazoles in trapping reactions with in situ-generated thiocarbonyl S-methanides derived from sterically crowded cycloaliphatic thioketones

• Grzegorz Mlostoń,
• Małgorzata Celeda,
• Marcin Palusiak,
• Heinz Heimgartner,
• Marta Denel-Bobrowska and
• Agnieszka B. Olejniczak

Beilstein J. Org. Chem. 2025, 21, 1508–1519, doi:10.3762/bjoc.21.113

• sulfur (χ = 2.55 (for C) and χ = 2.58 (for S) according to the Pauling scale), thiocarbonyl S-methanides 1 are considered as electron-rich 1,3-dipoles with basic and nucleophilic reactivity displayed by the =S+–CH2‒ unit [6]. Therefore, acidic compounds of type R–XH (X = NR’, O, S), which are able to

• heterocycles like saccharin and phthalimide, reacted with 1a and 1b yielding the corresponding N–H insertion products [13][14] (Scheme 1, lower part). In a recent publication, ring opening reactions of so-called D–A cyclopropanes (dimethyl 2-arylcyclopropane-1,1-dicarboxylates 3), initiated by a nucleophilic

Photoredox-catalyzed arylation of isonitriles by diaryliodonium salts towards benzamides

• Nadezhda M. Metalnikova,
• Nikita S. Antonkin,
• Tuan K. Nguyen,
• Natalia S. Soldatova,
• Alexander V. Nyuchev,
• Mikhail A. Kinzhalov and
• Pavel S. Postnikov

Beilstein J. Org. Chem. 2025, 21, 1480–1488, doi:10.3762/bjoc.21.110

• for unsymmetrical iodonium salts. Therefore, we moved to these to test the selectivity of aryl transfer under the established conditions. Since iodonium salts are prone to repeat the selectivity pattern of nucleophilic substitution in photoredox processes [35][36][37][38][39][40][41], we evaluated

Microwave-enhanced additive-free C–H amination of benzoxazoles catalysed by supported copper

• Andrei Paraschiv,
• Valentina Maruzzo,
• Filippo Pettazzi,
• Stefano Magliocco,
• Paolo Inaudi,
• Daria Brambilla,
• Gloria Berlier,
• Giancarlo Cravotto and
• Katia Martina

Beilstein J. Org. Chem. 2025, 21, 1462–1476, doi:10.3762/bjoc.21.108

• with the vessel pressurised under nitrogen (Table 2, entry 7). Under these conditions, the yield was 58%, demonstrating the superiority of an open vessel in a multimode cavity for this reaction. Since Cu salts facilitate both the nucleophilic attack of piperidine on benzoxazole to form the intermediate

• contrast, the presence of Cu facilitated the conversion of the intermediate to the desired aromatic benzoxazole 2a, demonstrating copper’s dual role as a Lewis acid in enhancing nucleophilic attack, and as an efficient catalyst for ring-closing oxidative rearomatisation. Of the conditions tested, the use