Substituent effects in N-acetylated phenylazopyrazole photoswitches

• Radek Tovtik,
• Dennis Marzin,
• Pia Weigel,
• Stefano Crespi and
• Nadja A. Simeth

Beilstein J. Org. Chem. 2025, 21, 830–838, doi:10.3762/bjoc.21.66

• triplet state [48], appear to play a role. Specifically, the rotation mechanism does not explain the low activation entropy observed in azobenzene systems [49] sparking new discussions on the possibility of alternative isomerization pathways [34]. Recently, Reimann et al. computationally showed that the

• involvement of a triplet state mechanism, which crosses the transition state for the Z→E relaxation, could explain the low values of the activation entropy. The same authors also showed experimental evidence for this proposal by an external heavy atom effect on Z→E isomerization. To understand the thermal Z→E

• activation enthalpy ΔH‡ and ΔS‡. In particular, NAc-PAP-CN showed a negative ΔS‡ = −30.0 ± 2.0 J/(mol·K), while NAc-PAP-OMe showed a relatively similar value (−39.0 ± 4.0 J/(mol·K)), hinting towards the same mechanism of relaxation operating for both compounds. Comparing these values to the calculations for

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

• or ketones. They used nickel foam as both anode and cathode electrodes in an undivided cell under air at room temperature. The reaction was carried out in the presence of KI as an electrolyte, a key additive, and acetone as a solvent. HI increases the reaction yield due to the activation of the

New advances in asymmetric organocatalysis II

• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 766–769, doi:10.3762/bjoc.21.60

• Radovan Sebesta Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia 10.3762/bjoc.21.60 Keywords: asymmetric organocatalysis; covalent activation; noncovalent activation; Organocatalysis is

• ]. Kowalczyk and co-workers showed how asymmetric organocatalysis can benefit from mechanochemical activation. They established that Michael additions of thiomalonates to enones, catalyzed by cinchona-derived primary amines, is efficient and enantioselective under ball-milling conditions [24]. Kondratyev and

• organocatalytic cycloaddition reactions of unsaturated imines. A broad variety of activation modes, as well as catalyst structures, was covered and found to be useful in affording a diverse array of chiral N-heterocycles [27]. In my group, we recently became interested in atroposelective catalytic syntheses

Development and mechanistic studies of calcium–BINOL phosphate-catalyzed hydrocyanation of hydrazones

• Carola Tortora,
• Christian A. Fischer,
• Sascha Kohlbauer,
• Alexandru Zamfir,
• Gerd M. Ballmann,
• Jürgen Pahl,
• Sjoerd Harder and
• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2025, 21, 755–765, doi:10.3762/bjoc.21.59

• and TMSCN (8). Model complex 4 initially reacts with TMSCN to give MeOTMS and HCN. Even under methanol-free conditions, an excess of TMSCN is therefore needed to achieve complete conversion (Table 1), which hints at a mechanism of catalyst activation through reaction of the metal complex with the

• the R-product from E-hydrazone is slightly lower in energy (Table 3). However, the activation barrier for the rate-limiting step is 0.4 kcal·mol−1 lower for the pathway shown in Figure 2 and that yields the S-product from the Z-hydrazone. As the activation barrier to thermal E/Z-isomerization is more

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

• 3αMan 5, first order reactions were assumed with the rate constants k5, k7, and k6 (Figure 2C). In order to determine the half-lifes τ1/2 and activation energies Ea of the photoswitching units comprised in the homobivalent glycocluster 6αMan3αMan 2, the decay of the metastable ZZ isomer to the

• k7 obtained with a first-order exponential decay fit (Table 2 and Supporting Information File 1, Figures S7, S9, and S11). The half-lifes τ1/2 and the activation energies Ea of thermal relaxation were calculated based on the determined rate constants. The kinetics show that thermal relaxation of the

• ), resulting half-lifes (τ1/2) and activation energies (Ea) for the thermal ZZ to EE isomerization of glycoclusters 1 [24] and 2 and thermal Z to E isomerization of the glycoantennas 3, 4, and 5 at 37 °C. The top-ranked results of the molecular modeling study of the various isomers of the ligands 6βGlc3αMan 1

Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

• -fluoroamide gauche effect has frequently been exploited is N-acylpyrrolidines, a structural motif found within many bioactive molecules (e.g., the fibroblast activation protein (FAP) inhibitors 111 and 112, Figure 12) [188][189][190][191][192]. When fluorinated analogues of N-acylpyrrolidines are prepared

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

• configurationally stable organoboron compounds was recently developed by Morken and co-workers, which employs only catalytic amounts of copper [47][48]. Their strategy uses chiral secondary organoboron compounds 20 as precursors to generate chiral alkylcopper species through a carefully controlled activation and

• transmetalation sequence (Scheme 6). For secondary boronic esters, Morken and co-workers conducted a systematic investigation to develop an efficient activation strategy [47]. Computational studies using DFT revealed an important relationship between the length of the boron–carbon bonds and the corresponding

• electronegativity, reaching 1.648 Å in the reactive alkoxytrialkyl complex D and 1.659 Å in the tetraalkyl "ate" complex E. The B–C bond lengths in amido- and alkyl-substituted boronic ester complexes B and C fell between these extremes, suggesting an intermediate level of activation. These findings prompted

Entry to 2-aminoprolines via electrochemical decarboxylative amidation of N‑acetylamino malonic acid monoesters

• Olesja Koleda,
• Janis Sadauskis,
• Darja Antonenko,
• Edvards Janis Treijs,
• Raivis Davis Steberis and
• Edgars Suna

Beilstein J. Org. Chem. 2025, 21, 630–638, doi:10.3762/bjoc.21.50

• -disubstituted piperidine-containing amino acid subunits. Likewise, a cyano-substituted cyclic aminal is a core structural unit of the fibroblast activation protein inhibitor 5 [3] (Figure 1). The widespread use of non-proteinogenic cyclic amino acids in drug discovery justifies both the design of new analogs

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