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

• products (products 2 to 5, Scheme 4). In other cases, under acidic and thermal conditions, DMSO can undergo a Pummerer-type process in which, upon activation of the sulfoxide oxygen, a reactive methyl(methylene)sulfonium ion (MMS) is formed (Scheme 5) that acts as an active electrophile. Depending on the

• ). Additionally, the Tiwari group developed a metal-free protocol using only K2S2O8 as an oxidant for the activation of DMSO to MMS (Scheme 8, path II) [38]. Under these conditions, an alternative mechanism arises in which the imine intermediate B, formed as previously stated through reaction between the aniline

• , methyl aryl ketones, and DMSO under iron(III) catalysis and using K2S2O8 for its activation [39]. The proposed mechanism is very close to those described above, with the methyl aryl ketone taking part of the reaction in place of the styrene component in the Povarov cyclization. In this case, the imine

Asymmetric synthesis of β-amino cyanoesters with contiguous tetrasubstituted carbon centers by halogen-bonding catalysis with chiral halonium salt

• Yasushi Yoshida,
• Maho Aono,
• Takashi Mino and
• Masami Sakamoto

Beilstein J. Org. Chem. 2025, 21, 547–555, doi:10.3762/bjoc.21.43

• , Japan; Grant-in-Aid for Early-Career Scientists (No. 22K14674) and Scientific Research (C) (No. 24K08424) from the Japan Society for the Promotion of Science; and the Leading Research Promotion Program “Soft Molecular Activation” of Chiba University, Japan.

Vinylogous functionalization of 4-alkylidene-5-aminopyrazoles with methyl trifluoropyruvates

• Judit Hostalet-Romero,
• Laura Carceller-Ferrer,
• Gonzalo Blay,
• Amparo Sanz-Marco,
• José R. Pedro and
• Carlos Vila

Beilstein J. Org. Chem. 2025, 21, 533–540, doi:10.3762/bjoc.21.41

• . Considering the high diastereoselectivity observed both in the presence and absence of the squaramide catalyst, we propose a plausible mechanism (Scheme 3) that involves hydrogen bonding activation of the methyl trifluoropyruvate by the NH₂ group of the aminopyrazole. This interaction directs the attack of

• electrophile activation. In certain reactions, we isolated compound A, the hydrate of methyl trifluoropyruvate. We hypothesized that preventing the formation of this byproduct could improve the reaction yield by using molecular sieves (entries 17 and 18, Table 1). However, when molecular sieves were added, the

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

• used to achieve higher yields [27]. Even in the absence of a transition-metal-based photosensitizer, a recent study showed that perfluoroalkylation using perfluoroalkyl iodides (RFI) could be carried out by activation of the RF–I bonds by formation of electron donor–electron acceptor complexes with an

• reactions) Dry Mg turnings (excess) were added to an oven-dried 100 mL Schlenk flask and mechanically activated via stirring and heating. After 1 h, dry THF (20 mL) and 9,10-ANTH(Br)2 (84 mg, 0.25 mmol) were added. Several activation methods were tried (ultra sonic bath, careful heating, addition of I2

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

• transfer [13][14][15]. Regardless of the mechanistic details of the activation manifold, all photochemical reactions obey two laws: the Grotthuss–Draper and the Einstein–Stark laws [16]. The Grotthuss–Draper law dictates that only absorbed light can induce photochemical transformations within a system. In

• mechanochemistry holds potential for unique opportunities for substrate activation while adopting an environmentally benign emerging technology (Figure 2, top). For example, it is well known that molecules in the solid state (or in very high concentration) often exhibit photophysical behaviors distinct from those

Beyond symmetric self-assembly and effective molarity: unlocking functional enzyme mimics with robust organic cages

• Keith G. Andrews

Beilstein J. Org. Chem. 2025, 21, 421–443, doi:10.3762/bjoc.21.30

• any charge generation requires that an equal and opposite charge be generated elsewhere, the unifying concept for polarization is that of “cooperative [4] bifunctionality”: providing opposing functionalities able to stabilize opposite charges: dual activation (e.g., the simultaneous activation of

• , therefore, that for redistribution penalties to be lessened, the equal and opposite stabilization must be granted to that same space. This is the basis of bifunctional/dual activation, as shown in Figure 1. Since very few reported supramolecular cavity designs provide bifunctional activation, cavity

• hydrophobic hosts [37]. Directed polarization, the basis for organocatalysis, is rare in cavity catalysis. Now, I believe the field of supramolecular catalysis to be on the cusp of putting these two elements – “organization and polarization” or “confinement and dual activation” – together with greater

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

• temperature or the activation entropy, hydrogen bonding, solvent [24], nature of the leaving groups and the promoter used [25]. The mechanism of glycosylation reactions has long been categorised mostly as dissociative SN1 reactions proceeding through stabilised oxocarbenium ions with the role of counterions

• levulinoyl protecting group, the 4,4-(ethylenedithio)pentanoyl group 28 [99]. Wong and co-workers illustrated the selective activation (Scheme 5) of C-2 levulinoyl-protected thiotolyl glycopyranosyl donor 29 for the synthesis of the disaccharide fragment 31 of fucosyl ganglioside GM1 [100]. Pivalate

• ) and 2-naphthylmethoxymethyl (NAPOM) derivatives [141][142]. Activation of the thiophenyl glycoside donors 78, protected by the alkoxymethyl groups at the C-2 position by a combination of NIS and In(OTf)3, followed by the nucleophilic attack of the acceptor glycoside 79 produced 1,2-trans glycosides

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

• acetone, allowing the pre-activation of the ruthenium complex with the successive release of an N-heterocyclic carbene ligand and a chlorine atom, which are replaced by two acetone molecules to form compound 2. Simultaneously, excitation of the osmium(II) complex in the red region (660 nm) decreases its

• , 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

• [4][5][6] and polymerization processes of unstable methylidene adducts [7][8][9], instead of the desired formation of a monocrotonic product. Therefore, heating [6][10][11][12][13][14] or Lewis acid activation [15][16][17][18] have often been used in the literature for successful multicomponent

Effect of substitution position of aryl groups on the thermal back reactivity of aza-diarylethene photoswitches and prediction by density functional theory

• Misato Suganuma,
• Daichi Kitagawa,
• Shota Hamatani and
• Seiya Kobatake

Beilstein J. Org. Chem. 2025, 21, 242–252, doi:10.3762/bjoc.21.16

• analysis of the thermal back reaction revealed activation parameters, highlighting how the substitution position of the aryl group affects the thermal stability. Additionally, density functional theory calculations identified M06 and MPW1PW91 as the most accurate functionals for predicting the thermal back

• theory in combination with the 6-31G(d) basis set well reproduces the experimental value of the activation energy for the thermal back reaction of various diarylbenzenes, resulting in the accurate prediction of the half-lifte time [58][63]. Thus, the combination of experiments and theoretical

• compounds N3, N4, and I1–I4. The activation enthalpy (ΔH‡) and activation entropy (ΔS‡) in the thermal reaction were determined from the intercept and slope. Using these values, the experimental activation free energy (ΔG‡(exp)), the k value, and the half-life (t1/2) at 298 K were calculated and the results

Streamlined modular synthesis of saframycin substructure via copper-catalyzed three-component assembly and gold-promoted 6-endo cyclization

• Asahi Kanno,
• Ryo Tanifuji,
• Satoshi Yoshida,
• Sota Sato,
• Saori Maki-Yonekura,
• Kiyofumi Takaba,
• Jungmin Kang,
• Kensuke Tono,
• Koji Yonekura and
• Hiroki Oguri

Beilstein J. Org. Chem. 2025, 21, 226–233, doi:10.3762/bjoc.21.14

• measurements (Figures S20 to S25, Supporting Information File 1). A notable feature of this cascade process is the temporary protection of the C≡N triple bond, nitrile in the key intermediate 11, by the 2,3-diaminobenzofuran group. This facilitates the site-selective activation of the alkyne triple bond by the

• activation of the alkyne triple bond and allows precise control of the chemo- and regioselectivities for the assembly of the left isoquinoline substructure. The unexpected discovery of the fluorescent intermediate 18 adds an intriguing dimension to our current synthetic investigation and suggests potential

Quantifying the ability of the CF₂H group as a hydrogen bond donor

• Matthew E. Paolella,
• Daniel S. Honeycutt,
• Bradley M. Lipka,
• Jacob M. Goldberg and
• Fang Wang

Beilstein J. Org. Chem. 2025, 21, 189–199, doi:10.3762/bjoc.21.11

• molecules bearing electron-donating methoxy groups are also weak HB donors (7b vs 1b). Furthermore, the cationic activation of HB donors is negligible when the quaternary nitrogen is para rather than ortho to the CF2H group (4 vs 5). These findings indicate that the presence of either a quaternary nitrogen

Recent advances in electrochemical copper catalysis for modern organic synthesis

• Yemin Kim and
• Won Jun Jang

Beilstein J. Org. Chem. 2025, 21, 155–178, doi:10.3762/bjoc.21.9

• achieved by precisely controlling the potential. Additionally, the merging of electrochemistry and transition-metal catalysis offers advantages in controlling substrate activation, intermediate reactivity, and bond formation, as well as facilitating asymmetric transformations. As a result, electrochemical

• efficient and economical approach for molecular synthesis [40]. This strategy has been widely applied in synthetic chemistry, the pharmaceutical industry, and materials science. Over the past few decades, transition-metal-catalyzed C–H activation reactions have been widely developed. Late-stage C–H

• functionalization of highly complex and diverse molecules, such as those of pharmaceuticals and natural products, has provided new retrosynthetic disconnections for complex compounds, contributing to improved resource efficiency [41][42][43][44][45][46]. Recently, the merging of C–H activation and electrochemistry

Nickel-catalyzed cross-coupling of 2-fluorobenzofurans with arylboronic acids via aromatic C–F bond activation

• Takeshi Fujita,
• Haruna Yabuki,
• Ryutaro Morioka,
• Kohei Fuchibe and
• Junji Ichikawa

Beilstein J. Org. Chem. 2025, 21, 146–154, doi:10.3762/bjoc.21.8

• , Ibaraki 305-8571, Japan Sagami Chemical Research Institute, 2743-1 Hayakawa, Ayase, Kanagawa 252-1193, Japan 10.3762/bjoc.21.8 Abstract 2-Fluorobenzofurans underwent efficient nickel-catalyzed coupling with arylboronic acids through the activation of aromatic C–F bonds. This method allowed us to

• coupling reactions of aromatic C–F and C–Br bonds with arylboronic acids. Keywords: arylboronic acid; benzofuran; C–F bond activation; cross-coupling; nickel; Introduction The metal-catalyzed activation of aromatic carbon–fluorine (C–F) bonds is widely recognized as a challenging task in synthetic

• organic chemistry owing to their high bond dissociation energy compared to other aromatic C–X (X = Cl, Br, I) bonds [1][2][3][4][5][6][7]. This activation is essential for the late-stage functionalization of stable C–F bonds in complex molecules with reactive functional groups, providing an orthogonal

Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• behavior or reactivity properties. The ambiguity related to the role of Cu(OTf)2 is particularly relevant for cycloaddition reactions, where it is even more difficult to justify the activation of the copper species as a Lewis acid or metal catalyst [12][13][14]. The reaction mechanism involved can be ionic

• to multiple C–C bonds generates extended carbon radicals capable of giving further functionalization. Regarding the ionic mechanism, the key step generally comprises the complexation with the unsaturated substrate leading to activation of the alkenyl/alkynyl moiety towards a nucleophilic attack. In

• some cases, activation of a carbonyl group by the copper catalyst to facilitate nucleophilic attack has also been reported. Moreover, both activations can be operative simultaneously. Since copper shows affinity either for multiple C–C bonds or polar functional groups, it seems the ideal tool for this

Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

• organocatalytic reactions are discussed according to the dominant catalyst activation mode. For covalent organocatalysis, the typical enamine and iminium modes are presented, followed by N-heterocyclic carbene-catalyzed reactions. The bulk of the review is devoted to non-covalent activation, where chiral Brønsted

• been prepared, which aims to provide an update on the last five years of this burgeoning area with some relevant links to key earlier works. The material in this article is divided according to the major activation mode of the organocatalyst, from covalent activation via enamine and iminium activation

• to NHC-catalyzed reactions. The major part is devoted to chiral Brønsted acid catalysis as it seems so far the most widely used activation principle for the generation of axially chiral compounds. Hydrogen-bond-donating catalysts and various other activation modes complete the discussion of recent

Emerging trends in the optimization of organic synthesis through high-throughput tools and machine learning

• Pablo Quijano Velasco,
• Kedar Hippalgaonkar and
• Balamurugan Ramalingam

Beilstein J. Org. Chem. 2025, 21, 10–38, doi:10.3762/bjoc.21.3

• reactant and to feed this information back to the pump for immediate quenching of carbonyldiimidazole to prevent any side reactions. The entire process allows to control the acid activation and amide formation precisely to afford the desired final product in quantitative yield. Recently, Sagmeister et al

Giese-type alkylation of dehydroalanine derivatives via silane-mediated alkyl bromide activation

• Perry van der Heide,
• Michele Retini,
• Fabiola Fanini,
• Giovanni Piersanti,
• Francesco Secci,
• Daniele Mazzarella,
• Timothy Noël and
• Alberto Luridiana

Beilstein J. Org. Chem. 2024, 20, 3274–3280, doi:10.3762/bjoc.20.271

• radical activation, resulting in milder and safer reaction conditions [14][15][16]. Given the toxicity of tin-based compounds, there has been significant interest in developing alternative halogen-atom-transfer reagents. Borane, alkylamine, and silane compounds have emerged as effective XAT reagents upon

• photocatalytic activation (Figure 1b) [17][18][19][20][21]. A photocatalytic HAT or SET generates the corresponding boryl, α-amino or silyl radical, which can abstract a halogen atom from alkyl halides to form the corresponding alkyl radical. However, the use of TTMS as a XAT reagent had already been established

• concerning benzophenone hydrogen-atom transfer and silane-mediated activation of alkyl bromides to perform a photochemical Giese reaction, methyl 2-(1,3-dioxoisoindolin-2-yl)acrylate (1) and bromocyclohexane (2) were dissolved in CH3CN (0.1 M) together with a stoichiometric amount of tris(trimethylsilyl

Efficient synthesis of fluorinated triphenylenes with enhanced arene–perfluoroarene interactions in columnar mesophases

• Yang Chen,
• Jiao He,
• Hang Lin,
• Hai-Feng Wang,
• Ping Hu,
• Bi-Qin Wang,
• Ke-Qing Zhao and
• Bertrand Donnio

Beilstein J. Org. Chem. 2024, 20, 3263–3273, doi:10.3762/bjoc.20.270

• commercial perfluoroarene chemical blocks and reagents, involving catalyzed C–F-bond activation and cross-coupling reactions, usually requiring precious transition-metal catalysts and tedious synthetic routes [28][29][30][31][32][33][34]. Therefore, low-cost and facile synthetic strategies are desired to

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• out IEDADA reactions has been a glowing field in recent years [11][12]. In particular, organocatalysis can provide different activation modes to promote enantioselective IEDADA reactions [13][14], based on three strategies (Figure 3): i) LUMO-lowering activation (Brønsted acid catalysis), ii) HOMO

• -raising activation (amine-based catalysis and N-heterocyclic carbenes), and iii) LUMO-lowering and HOMO-raising activation (bifunctional thioureas and squaramides). Due to the ubiquitous nature of non-covalent interactions in organic systems, they can play a decisive role in asymmetric transformations [15

• -derived azadiene by H-bonding. This dual activation promotes a stereoselective addition of 3-chlorooxindole to the azadiene leading to intermediate A. The latter is also activated by the chiral guanidine and undergoes an intramolecular nucleophilic substitution which delivers the product 19b with the

Synthesis of 2H-azirine-2,2-dicarboxylic acids and their derivatives

• Anastasiya V. Agafonova,
• Mikhail S. Novikov and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2024, 20, 3191–3197, doi:10.3762/bjoc.20.264

• situation. Dibenzyl ester 11c was prepared using traditional activation of carboxylic acid 6a, although the yield was only 23%. A higher yield of the branched ester 11d (86%, as a mixture of diastereomers) was obtained by carbene insertion, generated by blue LED irradiation of methyl 2-diazo-2-phenylacetate

• reaction of more branched alcohols failed. Such esters could be prepared from the dicarboxylic acids using traditional activation or OH-insertion reaction of carbenes formed by irradiation of the appropriate diazo compound. Approaches to 2H-azirine-2,2-dicarboxylic acid derivatives. Synthesis of 2H-azirine

Direct trifluoroethylation of carbonyl sulfoxonium ylides using hypervalent iodine compounds

• Radell Echemendía,
• Carlee A. Montgomery,
• Fabio Cuzzucoli,
• Antonio C. B. Burtoloso and
• Graham K. Murphy

Beilstein J. Org. Chem. 2024, 20, 3182–3190, doi:10.3762/bjoc.20.263

• ]. This synthetic potential has been demonstrated in a range of insertions into polar bonds [17][18][19][20], C−H activation transformations [21][22][23], and geminal difunctionalizations [24][25]. Within the literature, a broad array of classical methods describes the synthesis of sulfoxonium ylides [26

• ° and C–I bond lengths of 2.1 Å (I–CH2CF3) and 3.2 Å. Finally, a 37.8 kcal/mol activation energy between XB-2 and B for path 1 was calculated. On the other hand, path 2 had a much lower Gibbs free energy of activation of 24.3 kcal/mol, where the angle of attack from 1a to 2a’ was found at approximately

• 160° with equal C–I bond lengths of 2.5 Å in the transition state. The significantly lower activation energy allowed us to conclude that the SN2 mechanism was the more favourable pathway. Conclusion In conclusion, we have developed a direct polyfluoroalkylation reaction of sulfoxonium ylides. The

Controlled oligomerization of [1.1.1]propellane through radical polarity matching: selective synthesis of SF₅- and CF₃SF₄-containing [2]staffanes

• Jón Atiba Buldt,
• Wang-Yeuk Kong,
• Yannick Kraemer,
• Masiel M. Belsuzarri,
• Ansh Hiten Patel,
• James C. Fettinger,
• Dean J. Tantillo and
• Cody Ross Pitts

Beilstein J. Org. Chem. 2024, 20, 3134–3143, doi:10.3762/bjoc.20.259

• , alternatively, INT1 could be added to another equiv of 1 via TS2 to form INT2. Although formation of 4 is notably more thermodynamically favorable than INT2 (ΔΔG = −9.2 kcal/mol), a small difference in activation free energy is predicted (ΔΔG‡ = −1.4 kcal/mol). This, at least in part, provides an explanation as

• here that the free energy of activation is lower for chlorination, albeit only by 0.4 kcal/mol. This is consistent with the notion that the kinetic preference can be overcome by increasing the concentration of 1 relative to CF3SF4Cl. In the second product-determining step, Cl atom abstraction by INT5

• activation alone. Overall, our results suggest that this alternating polarity matching effect is subtle and subject to mitigation yet can lead to desirable products if employed thoughtfully. Lastly, following our synthetic and computational studies, accessing a CF3SF4-containing [2]staffane in good yield and

Hypervalent iodine-mediated intramolecular alkene halocyclisation

• Charu Bansal,
• Oliver Ruggles,
• Albert C. Rowett and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 3113–3133, doi:10.3762/bjoc.20.258

• proposed by the authors (Scheme 3). Activation of the HVI reagent by H-bonding leads to ligand exchange to give an aminofluoro iodonium intermediate A. Cyclisation occurs via nitrogen attack on the alkene to then give aziridinium intermediate B. Subsequent nucleophilic attack by fluoride on the more

• aza-heterocycles were synthesised in good yields. The authors proposed a mechanism for the fluorocyclisation reactions (Scheme 6), which relies on the activation of the fluoro-iodane reagent 12 with the zinc catalyst. The activation enables better orbital overlap to occur with the π bond of the alkene

• on the alkene gave low yields of product. A mechanism was proposed involving the activation of iodosylbenzene 9 with BF3·Et2O to form an HVI intermediate that activates the alkene to form an iodonium species. Intramolecular nucleophilic attack of nitrogen, elimination of PhI and attack by fluoride

Advances in the use of metal-free tetrapyrrolic macrocycles as catalysts

• Mandeep K. Chahal

Beilstein J. Org. Chem. 2024, 20, 3085–3112, doi:10.3762/bjoc.20.257

• active groups for a variety of substrates, making their use as supramolecular organocatalysts based on bifunctional activation mechanism (hydrogen-bonding/Lewis basicity) highly promising. At the same time, additional functional groups that are required for the catalysis can be easily installed on the

• acetonitrile, calix[4]pyrrole enhanced its solubility, contributing to its indirect activation. Various control experiments, such as using CuI with and without calix[4]pyrrole and using dipyrromethane as another potential co-catalyst, have confirmed the role of calix[4]pyrrole as a promoter. Recently

• activation of both substrates via hydrogen-bonding interactions. Additionally, these macrocycles showed excellent activity for sulfa-Michael additions, as well as a moderate activity for Henry and aza-Henry reactions. These results are consistent with the observation reported by Senge and co-workers