Recent advances in controllable/divergent synthesis

• Jilei Cao,
• Leiyang Bai and
• Xuefeng Jiang

Beilstein J. Org. Chem. 2025, 21, 890–914, doi:10.3762/bjoc.21.73

• environment around the copper center disfavors a direct interaction with nucleophilic alkyl radicals. Instead, the reaction proceeds via an outer-sphere mechanism, where the alkyl radical reacts with the copper-activated C=N unsaturated bond, enabling stereocontrolled C(sp3)–C(sp3) coupling. In contrast, with

• C(sp3)–C(sp3) coupling via distal stereocontrol, efficiently producing C3-alkylated pyrrolidines, while the nickel catalytic system afforded C2-alkylated pyrrolidines through a tandem alkene isomerization/hydroalkylation process. This method utilized readily accessible catalysts, chiral BOX ligands

• insertion to achieve C3 selectivity, whereas nickel catalysis involved alkene isomerization to generate a (2,3-dihydropyrrolyl) intermediate Int-35, followed by C2-selective coupling. In 2024, the Zheng group reported a catalyst-controlled cyclization reaction of bicyclo[1.1.0]butanes (BCBs) 32 with α

Cu–Bpin-mediated dimerization of 4,4-dichloro-2-butenoic acid derivatives enables the synthesis of densely functionalized cyclopropanes

• Patricia Gómez-Roibás,
• Andrea Chaves-Pouso and
• Martín Fañanás-Mastral

Beilstein J. Org. Chem. 2025, 21, 877–883, doi:10.3762/bjoc.21.71

• carboboration of unsaturated hydrocarbons [1][2][3][4][5][6][7]. In the course of our investigation of the copper-catalyzed borylative coupling of alkynes with allylic gem-dichlorides [3], we observed that alkyl 4,4-dichloro-2-butenoates deviated from the general reactivity trend. While allylic gem-dichlorides

• bearing aromatic and aliphatic substituents efficiently provided the allylboration product (Scheme 1a), the use of ester derivative 1 under same reaction conditions led to the formation of an unexpected product arising from the coupling of two dichloride molecules with no alkyne incorporation (Scheme 1b

Light-enabled intramolecular [2 + 2] cycloaddition via photoactivation of simple alkenylboronic esters

• Lewis McGhie,
• Hannah M. Kortman,
• Jenna Rumpf,
• Peter H. Seeberger and
• John J. Molloy

Beilstein J. Org. Chem. 2025, 21, 854–863, doi:10.3762/bjoc.21.69

• excitation [66][67], product derivatization was explored (Scheme 2A). While initial efforts for oxidation proved challenging, due to a competing retro-aldol ring-opening reaction, employing a buffered system enabled access to β-alcohol 5. Given the previous power of trifluoroborates in cross-coupling

Chitosan-supported CuI-catalyzed cascade reaction of 2-halobenzoic acids and amidines for the synthesis of quinazolinones

• Xuhong Zhao,
• Weishuang Li,
• Mengli Yang,
• Bojie Li,
• Yaoyao Zhang,
• Lizhen Huang and
• Lei Zhu

Beilstein J. Org. Chem. 2025, 21, 839–844, doi:10.3762/bjoc.21.67

• , which acts as a base. Subsequently, I undergoes oxidative addition and complexation with the amidine 2 to generate intermediate II. This intermediate then undergoes reductive elimination to form intermediate III, releasing CS@CuI back into the system. Finally, the coupling reaction between the carboxyl

4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches

• Nguyen Tran Nguyen,
• Vo Viet Dai,
• Luc Van Meervelt,
• Do Thi Thao and
• Nguyen Minh Thong

Beilstein J. Org. Chem. 2025, 21, 817–829, doi:10.3762/bjoc.21.65

• , show geminal coupling to each other [19]. However, in the 1H NMR spectrum of product 5a the above peaks were absent and the appearance of a new doublet at 2.76 ppm representing three protons from the methyl group (CH3) is observed. In addition, the 2D 1H–1H COSY NMR spectrum of 5a exhibited spin–spin

• coupling between the secondary amino proton and the proton resonance at 2.76 ppm (see Supporting Information File 1). Therefore, the doublet resonance signal at 2.76 ppm correlates to three protons from the methyl group (CH3) directly bonded to the nitrogen atom of the secondary amino group (NH

Synthesis and photoinduced switching properties of C₇-heteroatom containing push–pull norbornadiene derivatives

• Daniel Krappmann and
• Andreas Hirsch

Beilstein J. Org. Chem. 2025, 21, 807–816, doi:10.3762/bjoc.21.64

• a subsequent Suzuki cross-coupling reaction with (4-(diphenylamino)phenyl)boronic acid was performed. The reaction conditions were adapted from prior experiments with C-NBD1 [40] and further refined for the heterocyclic analogues. Optimal results were achieved using K2CO3, Pd(OAc)2 and RuPhos with

Recent advances in the electrochemical synthesis of organophosphorus compounds

• Babak Kaboudin,
• Milad Behroozi,
• Sepideh Sadighi and
• Fatemeh Asgharzadeh

Beilstein J. Org. Chem. 2025, 21, 770–797, doi:10.3762/bjoc.21.61

• amides with electron-withdrawing or electron-donating groups on their aromatic ring, producing products with yields ranging from 51% to 82%. In 2023, Lei and co-workers [47] reported an electrochemical C–P bond formation via a coupling reaction of C–H bonds of alkynes, alkenes, and aryl compounds with

• dialkyl phosphonates at carbon and platinum electrodes as the anode and cathode in the presence of a silver catalyst in a divided cell (Scheme 3). According to the report, the silver catalyst is central to the coupling reaction. The study of the effect of alternating current (a.c.) electrolysis parameters

• ferrocene and ruthenocene via coupling reaction. This method provides an efficient and versatile synthetic approach for producing phosphorylated metallocenes but also aids in interpreting the regioselectivity and reactivity of C−H functionalization in unsymmetric metallocenes. They used a platinum electrode

Orthogonal photoswitching of heterobivalent azobenzene glycoclusters: the effect of glycoligand orientation in bacterial adhesion

• Leon M. Friedrich and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2025, 21, 736–748, doi:10.3762/bjoc.21.57

• and excellent yield of 94% (Scheme 1). A chemoselective deprotection of the mannosyl thioacetate 7 to yield the glycosyl thiol 8 was achieved using 0.95 equivalents of sodium carbonate. The crude product was in turn submitted to a Buchwald–Hartwig–Migita cross-coupling reaction [33] with the

• azobenzene derivative 9 [34] to furnish 10. This reaction had to be carried out at −78 °C in order to suppress nucleophilic substitution of the ortho-fluorine substituents in 9 by the thiol 8, a reaction that competes with the desired cross-coupling. For the second Buchwald–Hartwig–Migita cross-coupling, the

• 3-O-(mannosyloxyazobenzene)-6-thio-mannoside 11 was employed, which was prepared according to a known procedure applied for the synthesis of the heterobivalent glycocluster 6βGlc3αMan 1 (cf. Supporting Information File 1, Scheme S1). The cross-coupling of thiol 11 with the azobenzene

Synthesis of HBC fluorophores with an electrophilic handle for covalent attachment to Pepper RNA

• Raphael Bereiter and
• Ronald Micura

Beilstein J. Org. Chem. 2025, 21, 727–735, doi:10.3762/bjoc.21.56

• provide fluorophore 19. Subsequent palladium-catalyzed cross-coupling with tributyl(vinyl)tin resulted in the installation of the vinyl group (compound 20). Finally, cleavage of the silyl ether gave the free alcohol 21, which was converted into the corresponding mesyloxypropyl HBC ligand 22. The

Photochemically assisted synthesis of phenacenes fluorinated at the terminal benzene rings and their electronic spectra

• Yuuki Ishii,
• Minoru Yamaji,
• Fumito Tani,
• Kenta Goto,
• Yoshihiro Kubozono and
• Hideki Okamoto

Beilstein J. Org. Chem. 2025, 21, 670–679, doi:10.3762/bjoc.21.53

• was obtained by a Migita–Kosugi–Stille coupling between bromophenanthrene 15 and (E)-1,2-bis(tributylstannyl)ethene to afford diarylethene 18 followed by Mallory photoreaction. The obtained intermediate 18 contained residual palladium and isolation was not successful due to its poor solubility in

Recent advances in allylation of chiral secondary alkylcopper species

• Minjae Kim,
• Gwanggyun Kim,
• Doyoon Kim,
• Jun Hee Lee and
• Seung Hwan Cho

Beilstein J. Org. Chem. 2025, 21, 639–658, doi:10.3762/bjoc.21.51

• AAA methodologies. Review Copper-catalyzed stereospecific coupling of chiral organometallic species with allylic electrophiles The asymmetric construction of carbon–carbon bonds through copper-catalyzed AAA has emerged as a powerful synthetic tool in organic chemistry [41][42][43][44][45]. The

• organolithium species and the other employing chiral organoboron compounds. Copper-mediated stereospecific coupling of chiral organolithium species with allylic electrophiles In the organolithium approach, a breakthrough was achieved by Knochel and co-workers through carefully controlled reaction conditions

• stereochemical integrity. Through these careful experimental controls, Knochel and co-workers effectively addressed the long-standing challenge of handling these traditionally unstable chiral organometallic intermediates. Copper-catalyzed stereospecific coupling of chiral organoboron species with allylic

Photocatalyzed elaboration of antibody-based bioconjugates

• Marine Le Stum,
• Eugénie Romero and
• Gary A. Molander

Beilstein J. Org. Chem. 2025, 21, 616–629, doi:10.3762/bjoc.21.49

• covalent bioconjugation. Effective bioconjugation has been dramatically facilitated by the development of robust bioorthogonal reactions, which has revolutionized the field of chemical biology [17]. A bioorthogonal reactive group can be introduced into proteins via direct chemical coupling on specific

• native amino acids, by enzymatic coupling, or by bioengineering for the incorporation of non-canonical amino acids [18][19]. In fact, incorporating non-natural amino acids significantly broadens the scope of reactions that can be used in bioconjugation. As an example, click chemistry comprises one

• particularly useful and important tool in which azides and other dipolar species engage with reactive alkenes and alkynes on non-canonical amino acids [20]. Transition-metal-mediated processes, including metathesis reactions, aryl cross-coupling reactions, and conjugate addition reactions with dehydroalanine

Semisynthetic derivatives of massarilactone D with cytotoxic and nematicidal activities

• Rémy B. Teponno,
• Sara R. Noumeur and
• Marc Stadler

Beilstein J. Org. Chem. 2025, 21, 607–615, doi:10.3762/bjoc.21.48

• recorded in deuterated solvents (CDCl3 and acetone-d6) with an Avance III 700 (Bruker, Billerica, MA, USA) (1H: 700 MHz, 13C: 175 MHz) and an Avance III 500 (Bruker, Bremen, Germany) (1H: 500 MHz, 13C: 125 MHz) spectrometers. Chemical shifts are given in parts per million (ppm), and coupling constants in

Formaldehyde surrogates in multicomponent reactions

• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Bernhard Westermann

Beilstein J. Org. Chem. 2025, 21, 564–595, doi:10.3762/bjoc.21.45

• et al. developed a three-component Mannich-type reaction under oxidative and catalytic conditions that allows the coupling of aryl ketones 18 and saccharine (19) using DMSO as the solvent and the source for a methylene bridge linking the two building blocks (Scheme 15) [49]. Following this strategy

• available from the reaction between aldehydes and amines (primary or secondary), the reaction is called AAA coupling: amine–aldehyde–alkyne coupling (Scheme 19). In this context, the use of formaldehyde as a C1 building block is suitable despite the unstable aminol intermediate. There are several examples

• showing how formaldehyde or paraformaldehyde can be used in the AAA coupling of three components for the synthesis of propargylamines [58][59][60][61]. However, the problems associated with the stability of the imine/enamine intermediate generated from formaldehyde must still be addressed. Several

Deep-blue emitting 9,10-bis(perfluorobenzyl)anthracene

• Long K. San,
• Sebastian Balser,
• Brian J. Reeves,
• Tyler T. Clikeman,
• Yu-Sheng Chen,
• Steven H. Strauss and
• Olga V. Boltalina

Beilstein J. Org. Chem. 2025, 21, 515–525, doi:10.3762/bjoc.21.39

• -step reactions with anthraquinone starting materials [24], or by Ullman coupling reactions of acene bromides with perfluoroalkyl iodides [25]. Notably, direct UV photoinduced reactions between anthracene and perfluoroalkyl iodides in the presence of a reducing agent, Na2S2O3, yielded perfluoroalkylated

• and C6F5 moieties appeared in the expected regions of −δ = 71–74 ppm and −δ = 140–165 ppm, respectively. Through-space F–F coupling was observed between the CF2 group and the ortho-F atoms, resulting in a triplet and a multiplet, respectively. Using 1,4-C6H4(CF3)2 as an internal standard, the F/H mole

• the long ANTH axis (Figure S5 in Supporting Information File 1). This insulation further inhibits any electronic coupling between the columns. Having effectively zero π–π overlap should result in reduced electronic coupling between molecules, which may be a beneficial factor for OLED applications

Synthesis of the aggregation pheromone of Tribolium castaneum

• Biyu An,
• Xueyang Wang,
• Ao Jiao,
• Qinghua Bian and
• Jiangchun Zhong

Beilstein J. Org. Chem. 2025, 21, 510–514, doi:10.3762/bjoc.21.38

• is a destructive stored product pest. The aggregation pheromone of this pest was prepared via a new and effective strategy. The key steps include the ring-opening reaction of chiral 2-methyloxirane, the stereospecific inversion of chiral secondary tosylate, Li2CuCl4-catalyzed coupling of tosylate

• coupling, and finally leads to the target pheromones by olefin oxidation with RuCl3/NaIO4. Results and Discussion The retrosynthetic analysis of the aggregation pheromone (4R,8R)-1 is shown in Scheme 1. Obviously, the target pheromone (4R,8R)-1 could be synthesized via an oxidation of chiral terminal

• olefine (5R,9R)-12, which could be obtained through Li2CuCl4-catalyzed coupling of chiral tosylate (S)-10 with a Grignard reagent derived from (R)-1-bromo-2-methylbutane ((R)-11). The key chiral building block (S)-10 was envisaged to be prepared through a sequence of hydrolyzation, decarboxylation, borane

Synthesis of N-acetyl diazocine derivatives via cross-coupling reaction

• Thomas Brandt,
• Pascal Lentes,
• Jeremy Rudtke,
• Michael Hösgen,
• Christian Näther and
• Rainer Herges

Beilstein J. Org. Chem. 2025, 21, 490–499, doi:10.3762/bjoc.21.36

• switching efficiency in aqueous solutions. In order to investigate the chemistry of this promising photoswitch and to unlock further applications, we now investigate strategies for the synthesis of derivatives, which are based on cross-coupling reactions. Fourteen vinyl-, aryl-, cyano-, and amino

• -substituted diazocines were prepared via Stille, Suzuki, and Buchwald–Hartwig reactions. X-ray structures are presented for derivatives 1, 2 and 7. Keywords: cross-coupling; diazocine; N-acetyl diazocine; photoisomerization; photoswitch; thermal relaxation; Introduction Diazocines are frequently used

• substitution. Substituents such as halogen atoms must be introduced into the N-acetyl diazocine structure during the synthesis of the building blocks. In the present work we start from mono- and dihalogenated N-acetyl diazocine 2–4 (Figure 2) and focus on the further derivatization via cross-coupling reactions

Organocatalytic kinetic resolution of 1,5-dicarbonyl compounds through a retro-Michael reaction

• James Guevara-Pulido,
• Fernando González-Pérez,
• José M. Andrés and
• Rafael Pedrosa

Beilstein J. Org. Chem. 2025, 21, 473–482, doi:10.3762/bjoc.21.34

• organometallic catalysis [15], enzymatic catalysis [16], aminocatalysis [17][18][19], and hydrogen-bonding catalysis [20][21][22]. The Michael addition reaction is a versatile synthetic methodology that allows the formation of new carbon–carbon and carbon–heteroatom bonds through the coupling of electron-poor

Photomechanochemistry: harnessing mechanical forces to enhance photochemical reactions

• Francesco Mele,
• Ana M. Constantin,
• Andrea Porcheddu,
• Raimondo Maggi,
• Giovanni Maestri,
• Nicola Della Ca’ and
• Luca Capaldo

Beilstein J. Org. Chem. 2025, 21, 458–472, doi:10.3762/bjoc.21.33

• . Also in this case, the addition of toluene was beneficial and excellent yield of the corresponding product (10.2) was observed in 30 h of reaction. As a comparison, the latter reaction required 48 h in solution. Intriguingly, 10.3 could in turn be synthesized via a mechanochemical Suzuki coupling

• benefits of the photomechanochemical approach in the field of synthesis [77]. Specifically, they developed photomechanochemical conditions for the atom-transfer-radical addition (ATRA) of sulfonyl chlorides to alkenes, pinacol coupling of carbonyl compounds, decarboxylative acylation, and photocatalyzed [2

• traditional solution-phase synthesis. In fact, in the latter case, almost complete recovery of the starting material was observed. Second, the authors found that the replacement of diisopropylethylamine (DIPEA) with Hantzsch ester in the role of sacrificial reductant for the pinacol coupling of benzaldehyde

New tandem Ugi/intramolecular Diels–Alder reaction based on vinylfuran and 1,3-butadienylfuran derivatives

• Yuriy I. Horak,
• Roman Z. Lytvyn,
• Andrii R. Vakhula,
• Yuriy V. Homza,
• Nazariy T. Pokhodylo and
• Mykola D. Obushak

Beilstein J. Org. Chem. 2025, 21, 444–450, doi:10.3762/bjoc.21.31

• products were identified via NMR as 4,4a,5,6,7,7a-hexahydro-3aH-furo[2,3-f]isoindoles. The structures of compounds 5 were confirmed by NMR spectroscopy data (for details and discussion see Supporting Information File 1). The NMR data for the obtained furoindole skeleton signals and spin-coupling constants

The effect of neighbouring group participation and possible long range remote group participation in O-glycosylation

• Rituparna Das and
• Balaram Mukhopadhyay

Beilstein J. Org. Chem. 2025, 21, 369–406, doi:10.3762/bjoc.21.27

• glycosylation reaction between the two extremes of substitution reactions enables the synthetic chemists to manoeuvre and design the coupling reactions according to the regio- and stereochemical demand. In chemical glycosylation, the role of protecting groups in directing the attack of the incoming nucleophile

Synthesis, characterization, antimicrobial, cytotoxic and carbonic anhydrase inhibition activities of multifunctional pyrazolo-1,2-benzothiazine acetamides

• Ayesha Saeed,
• Shahana Ehsan,
• Muhammad Zia-ur-Rehman,
• Erin M. Marshall,
• Sandra Loesgen,
• Abdus Saleem,
• Simone Giovannuzzi and
• Claudiu T. Supuran

Beilstein J. Org. Chem. 2025, 21, 348–357, doi:10.3762/bjoc.21.25

• complex as the amide coupling agent with thionyl chloride [38] (Figure 1C). Recently, benzothiazine scaffolds of phenyl acetamides were synthesized as potent inhibitors for ureolytic infections [39] (Figure 1D). Saccharine (a sweetener) was reported to be a potent carbonic anhydrase inhibitor (CAI) by

• pain [48], cancer [41], hypertension (as diuretics) [41], and arthritis [49]. This article introduces a new approach to synthesize the targeted scaffolds from commercially available saccharine without using amide coupling agents to minimize the cost. This work is the first attempt to put pyrazolo-1,2

• . Finally, none of the pyrazolobenzothiazine scaffolds showed hCA inhibition activity comparable to acetazolamide (AAZ, reference drug). Conclusion In summary, an economical multistep synthesis approach without using any coupling reagents for the synthesis of new multifunctional pyrazolo-1,2-benzothiazines

Red light excitation: illuminating photocatalysis in a new spectrum

• Lucas Fortier,
• Corentin Lefebvre and
• Norbert Hoffmann

Beilstein J. Org. Chem. 2025, 21, 296–326, doi:10.3762/bjoc.21.22

• sustainable photocatalysis, with applications ranging from selective oxidation to cross-dehydrogenative coupling. These organic systems are valued for their reduced environmental impact, their wide availability, and tunability, making them viable alternatives to traditional metal-based catalysts for red-light

• + and 660 nm for [Os(phen)3]2+ [15]. In a same way, spin–orbit coupling, stemming from the relativistic effects, can be exploited in photoredox-catalyzed reaction [16]. Spin–orbit coupling promotes intersystem crossing (ISC) between the singlet and triplet excited states, and even allows for direct

• , thereupon highlighting potential for broad applications in photoredox catalysis on an industrial scale. In this context, T. Rovis et al. have studied a C–N cross-coupling Buchwald–Hartwig-like reaction using dual nickel and osmium catalysis under red-light activation, addressing common challenges such as

Three-component reactions of conjugated dienes, CH acids and formaldehyde under diffusion mixing conditions

• Dmitry E. Shybanov,
• Maxim E. Kukushkin,
• Eugene V. Babaev,
• Nikolai V. Zyk and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2025, 21, 262–269, doi:10.3762/bjoc.21.18

• alcohol 2. Its 1H NMR spectrum contained a triplet with a coupling constant of 5.1 Hz at 5.52 ppm and a doublet at 4.30 ppm. In methanol, ethanol and petroleum ether, with an increasing reaction time, a significant amount of product 3 was observed in the 1H NMR spectra of the mixtures, as identified by

Synthesis of disulfides and 3-sulfenylchromones from sodium sulfinates catalyzed by TBAI

• Zhenlei Zhang,
• Ying Wang,
• Xingxing Pan,
• Manqi Zhang,
• Wei Zhao,
• Meng Li and
• Hao Zhang

Beilstein J. Org. Chem. 2025, 21, 253–261, doi:10.3762/bjoc.21.17

• antibody–drug coupling (ADCs), in which the active drug released in the target cell by selectively breaking the disulfide bond [11]. Given the wide applicability of disulfides, the development of efficient, green, mild, and cost-effective methods for the organic synthesis of disulfides is of significant

• reaction at 120 °C for 2 hours were determined as optimal conditions for the reaction (Table 1, entry 14). Under the optimized conditions, the coupling reaction of various sodium arylsulfinates was investigated to assess the scope and generality of this protocol. The results, shown in Scheme 2