Tautomerism and switching in 7-hydroxy-8-(azophenyl)quinoline and similar compounds

• Lidia Zaharieva,
• Vera Deneva,
• Fadhil S. Kamounah,
• Nikolay Vassilev,
• Ivan Angelov,
• Michael Pittelkow and
• Liudmil Antonov

Beilstein J. Org. Chem. 2025, 21, 1404–1421, doi:10.3762/bjoc.21.105

• on the substitution in the 7OHQ moiety. The relative energies of K in respect of E under various substitution in 7OHQ are collected in Tables S3 (Supporting Information File 1) and the directions of change are illustrated in Figure 8a. It seems that substitution on positions 2 (with exception of a

• substitution in the 7OHQ part of 1 is illustrated in Figure 8b–d and the corresponding values are collected in Table S4, Supporting Information File 1. In 1 all three criteria for clean switching are not fulfilled and it is interesting to see how the substitution can change the situation. In respect of ΔE(K-E

• on position 4 lead to changes in the desired direction. The substitution on positions 5 and 6 leads to strong stabilization of KE, which is not needed. The cyano group on position 5 destabilizes KE strongly. The value of ΔE(KK-K) has also to be larger than 2 and, as seen from Figure 8d, it cannot be

Oxetanes: formation, reactivity and total syntheses of natural products

• Peter Gabko,
• Martin Kalník and
• Maroš Bella

Beilstein J. Org. Chem. 2025, 21, 1324–1373, doi:10.3762/bjoc.21.101

• discussed in more detail and illustrated by specific examples. 1.1 C–O bond-forming cyclisations 1.1.1 Intramolecular Williamson etherifications: Discovered by Alexander Williamson in 1850, this reaction is an SN2 substitution in which a leaving group, typically a halide or sulphonate ester, is displaced by

• methods for oxetane synthesis, mainly due to its practicality and versatility. 1.1.1.1 Substitution of a leaving group: In 2017, Moody et al. developed a new route towards spiro-oxetanes 8 utilising a combination of 1,4-C–H insertion and Williamson etherification (Scheme 3) [38]. The methodology commences

• and colleagues published a one-step synthesis of spirooxindole 2,2-disubstituted oxetanes 11 via an unprecedented addition/substitution cascade (Scheme 4) [39]. The protocol reacts readily available 3-hydroxyindolinones 9 with phenyl vinyl selenone (10) in aqueous KOH at room temperature and gives

Recent advances and future challenges in the bottom-up synthesis of azulene-embedded nanographenes

• Bartłomiej Pigulski

Beilstein J. Org. Chem. 2025, 21, 1272–1305, doi:10.3762/bjoc.21.99

• easily adapted to more modular approaches, limiting the variety of possible substitution patterns. This is why more modern approaches continue to be developed. Modern approaches to azulene-embedded nanographenes Modern synthetic approaches have greatly benefited from the discovery of palladium-catalysed

• bathochromically shifted compared to isomeric terrylenebisimide (λmax = 650 nm) [86] and even larger rylene bisimides like hexarylenebisimide (λmax = 953 nm) [87]. Bisimide 129 might be regioselectivily brominated using NBS, yielding PAH 130 in 80%. The bromide 130 undergoes nucleophilic substitution with

• methoxide or morpholine, giving the corresponding substitution products 131 and 132 in 60% and 74%, respectively. Very recently, during revision of this work, Aratani and co-workers reported the use of this strategy in the synthesis of two azulene-embedded isomers of perylene monoimide [88]. Cyclization of

Recent advances in oxidative radical difunctionalization of N-arylacrylamides enabled by carbon radical reagents

• Jiangfei Chen,
• Yi-Lin Qu,
• Ming Yuan,
• Xiang-Mei Wu,
• Heng-Pei Jiang,
• Ying Fu and
• Shengrong Guo

Beilstein J. Org. Chem. 2025, 21, 1207–1271, doi:10.3762/bjoc.21.98

• . This alkyl radical then adds across the C–C double bond in the enyne, forming an alkyl radical intermediate B, which reacts with the C–C triple bond to generate a vinyl radical intermediate C. Depending on the substitution effect at the 3-position of the acrylamide moiety, the intermediate undergoes

• substrate scope was extensively explored, demonstrating compatibility with various N-arylacrylamides and perfluoroalkyl iodides. N-Arylacrylamides with electron-donating and electron-withdrawing substituents (80a–e), as well as different substitution patterns on the aromatic ring, gave good to excellent

• cation B and an α-carbon radical A. The α-carbon radical A then undergoes intermolecular radical addition to the acrylamide, forming a new carbon-centered radical intermediate C, which subsequently undergoes intramolecular cyclization to yield the oxindole product 88a via homolytic aromatic substitution

Optimized synthesis of aroyl-S,N-ketene acetals by omission of solubilizing alcohol cosolvents

• Julius Krenzer and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2025, 21, 1201–1206, doi:10.3762/bjoc.21.97

• ) and electron-donating (-OMe) substituents were used. Additionally, a heterocycle could be incorporated. Different benzyl substituents were employed, and substitution at the benzothiazole core was also tolerated (Table 1). As an alternative to 1,4-dioxane, 2-methyltetrahydrofuran was tested the solvent

Synthesis of β-ketophosphonates through aerobic copper(II)-mediated phosphorylation of enol acetates

• Alexander S. Budnikov,
• Igor B. Krylov,
• Fedor K. Monin,
• Valentina M. Merkulova,
• Alexey I. Ilovaisky,
• Liu Yan,
• Bing Yu and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2025, 21, 1192–1200, doi:10.3762/bjoc.21.96

• substitution pattern in the aryl ring does not have a significant effect on the yield of 3 for both acceptor and donor derivatives, which shows the versatility of the developed protocol. However, among halogen-containing derivatives, higher yields were observed for bromine-substituted ones (products 3i and 3l

Selective monoformylation of naphthalene-fused propellanes for methylene-alternating copolymers

• Kenichi Kato,
• Tatsuki Hiroi,
• Seina Okada,
• Shunsuke Ohtani and
• Tomoki Ogoshi

Beilstein J. Org. Chem. 2025, 21, 1183–1191, doi:10.3762/bjoc.21.95

• ]. Widespread use of 3D π-skeletons requires not only efficient construction of the skeletons but also functionalization with precise control of substitution numbers and positions. Along this line, fully π-fused [4.4.4]- and [3.3.3]propellanes [40][41][42][43] were able to be brominated and nitrated at six

• same protocol was successfully applicable to pristine π-fused [3.3.3]propellane [3.3.3], giving [3.3.3]_CHO selectively in 67% yield (Table 1, entry 3). In electrophilic aromatic substitutions, multifold reactions are possible, and the number of substitution is sometimes difficult to control by tuning

Enhancing chemical synthesis planning: automated quantum mechanics-based regioselectivity prediction for C–H activation with directing groups

• Julius Seumer,
• Nicolai Ree and
• Jan H. Jensen

Beilstein J. Org. Chem. 2025, 21, 1171–1182, doi:10.3762/bjoc.21.94

• electrophilic aromatic substitution and a proton abstraction mechanism via CMD, where they calculated the relative energies of the intermediates. Using their workflow, they were able to predict correctly the regioselectivity for 18 tested substrates. The main limitation of this work is the computational cost

• groups following the CMD mechanism. This workflow employs (semi-empirical) quantum calculations in a hierarchical way to predict regioselective outcomes, delivering results within seconds to minutes. For substrates that are expected to follow the electrophilic aromatic substitution mechanism without the

• influence of DGs, we refer the reader to previous work done by Kromann et al. [15] and Ree and colleagues [16][17]. The there developed RegioSQM predicts the regioselectivity of reactions following the electrophilic aromatic substitution mechanism within seconds to minutes using a web interface or a Python

A multicomponent reaction-initiated synthesis of imidazopyridine-fused isoquinolinones

• Ashutosh Nath,
• John Mark Awad and
• Wei Zhang

Beilstein J. Org. Chem. 2025, 21, 1161–1169, doi:10.3762/bjoc.21.92

• (IMDA), and dehydrative re-aromatization reactions for the synthesis of imidazopyridine-fused isoquinolinones is developed. Gaussian computation analysis on the effect of the substitution groups for the IMDA reaction is performed to understand the reaction mechanism. Keywords: Groebke–Blackburn

• charge and the electronic consequences of the 5-Br substitution 6j were considered, which were found to inhibit the system from attaining the requisite conditions for successful cycloaddition. Secondly, the interatomic distances between the reactive centers of the diene and dienophile are almost similar

Synthetic approach to borrelidin fragments: focus on key intermediates

• Yudhi Dwi Kurniawan,
• Zetryana Puteri Tachrim,
• Teni Ernawati,
• Faris Hermawan,
• Ima Nurasiyah and
• Muhammad Alfin Sulmantara

Beilstein J. Org. Chem. 2025, 21, 1135–1160, doi:10.3762/bjoc.21.91

• iodide, and subsequent nucleophilic substitution with deprotonated (R,R)-91. The introduction of the OPMB functionality in compound 88 could then be achieved by following the steps employed in the transformation of 84 to 83. The synthesis via route A began with efforts to optimize the epimerization of

• . Herber and Breit’s strategy for constructing Theodorakis’ C3–C11 fragment In 2006, Herber and Breit utilized an iterative deoxypropionate synthesis to construct the Theodorakis’ C3–C11 fragment of borrelidin. This approach was based on a copper-mediated directed allylic substitution previously developed

• ]. Synthesis of Ōmura’s C1–C11 fragment 61 by Minnaard and Madduri [37]. Synthesis of fragment 62b of borrelidin as proposed by Minnaard and Madduri [37]. Iterative directed allylation for the synthesis of deoxypropionates by Herber and Breit [33]. Iterative copper-mediated directed allyl substitution for the

Investigations of amination reactions on an antimalarial 1,2,4-triazolo[4,3-a]pyrazine scaffold

• Henry S. T. Smith,
• Ben Giuliani,
• Kanchana Wijesekera,
• Kah Yean Lum,
• Sandra Duffy,
• Aaron Lock,
• Jonathan M. White,
• Vicky M. Avery and
• Rohan A. Davis

Beilstein J. Org. Chem. 2025, 21, 1126–1134, doi:10.3762/bjoc.21.90

• substitution; antimalarial; open source malaria; triazolopyrazine; 1,2,4-triazolo[4,3-a]pyrazines; Introduction Malarial disease is a potentially fatal, acute febrile illness caused by infection with any of several species of vector-borne apicomplexan parasites in the genus Plasmodium [1]. The African endemic

• -position (tele-substituted; Figure 1), distant from the halogen leaving group at position 5 [10]. A plausible reaction mechanism was proposed by Korsik et al. [10]. The antimalarial activity of series 4 triazolopyrazine scaffolds is generally reduced by substitution of an amine functionality at the 8

• )] corresponding to the four protons on the 4-chlorophenyl substituent of the starting material. Substitution with phenethylamine was confirmed by the presence of an ethylamino pendant chain, showing an exchangeable amine proton triplet at δH 8.30 (H-16, J = 5.8 Hz), which was COSY coupled to an ethyl spin system

Gold extraction at the molecular level using α- and β-cyclodextrins

• Susana Santos Braga

Beilstein J. Org. Chem. 2025, 21, 1116–1125, doi:10.3762/bjoc.21.89

• used to wash the gold precipitate by using the anti-solvent acetone. Thiolated β-CD derivative for selective gold precipitation Fang et al. reported the synthesis and application of a 6-thiolated β-CD derivative (with unspecified degree of substitution) to precipitate metallic gold from strongly acidic

Recent advances in synthetic approaches for bioactive cinnamic acid derivatives

• Betty A. Kustiana,
• Galuh Widiyarti and
• Teni Ernawati

Beilstein J. Org. Chem. 2025, 21, 1031–1086, doi:10.3762/bjoc.21.85

• (Scheme 21C) [55]. Kawabata and co-workers (2020) prepared the β-glycoside 66 from α-ᴅ-glucose and cinnamic acid (7) in good yield through the Mitsunobu reaction (Scheme 22) [56]. The 13C kinetic isotope effect experiment (KIE = 1.028) showed that the glycosylation proceeded via SN2 substitution (67). Sun

Pd-Catalyzed asymmetric allylic amination with isatin using a P,olefin-type chiral ligand with C–N bond axial chirality

• Natsume Akimoto,
• Kaho Takaya,
• Yoshio Kasashima,
• Kohei Watanabe,
• Yasushi Yoshida and
• Takashi Mino

Beilstein J. Org. Chem. 2025, 21, 1018–1023, doi:10.3762/bjoc.21.83

• palladium catalysts with amines as nucleophiles have been reported [14][15][16][17][18][19][20][21][22][23][24][25], there have been only a few reports on the N-substitution of isatin using asymmetric methods. Recently, Wolf’s group reported a transition-metal-catalyzed (Pd-catalyzed) asymmetric allylic

• ligands with axial chirality for Pd-catalyzed asymmetric allylic substitution reactions. For example, the Zhou group reported a P,olefin-type chiral ligand 3 with C–C bond axial chirality for this reaction (Figure 2) [27]. Additionally, we have recently reported chiral ligands with C–N bond axial

• chirality, such as N-alkyl-N-cinnamyl-type chiral ligands 4 [28][29] and 5 [30], and a P,olefin-type chiral ligand 6 [31] with a cinnamoyl group instead of a cinnamyl group. In particular, the chiral ligand 6 is effective in the Pd-catalyzed asymmetric allylic substitution reaction of allylic esters with

Synthesis of pyrrolo[3,2-d]pyrimidine-2,4(3H)-diones by domino C–N coupling/hydroamination reactions

• Ruben Manuel Figueira de Abreu,
• Robin Tiedemann,
• Peter Ehlers and
• Peter Langer

Beilstein J. Org. Chem. 2025, 21, 1010–1017, doi:10.3762/bjoc.21.82

• Abstract A variety of pyrrolo[3,2-d]pyrimidine-2,4(3H)-diones were prepared by a combination of Sonogashira reaction and subsequent cyclization by domino C–N coupling/hydroamination reaction. The optical properties (UV–vis absorption and fluorescence) depend on the substitution pattern of the compounds

• ]pyrimidine-2,4(3H)-diones 4 were investigated by steady-state absorption and photoluminescence spectroscopy (Figure 2, Table 2). The wavelength and intensity of absorption and emission depended on the substitution pattern. The methyl-substituted compound 4a showed one broad absorption band at ≈290 nm. A

• amino group. The corresponding fluorescence quantum yields were also strongly affected by the substitution pattern of the pyrrolouracils. Compounds 4k and 4l show very high fluorescence quantum yields of 83% and 71%, respectively, what might be reasoned by the strong donor ability of the NMe2-functional

Recent total synthesis of natural products leveraging a strategy of enamide cyclization

• Chun-Yu Mi,
• Jia-Yuan Zhai and
• Xiao-Ming Zhang

Beilstein J. Org. Chem. 2025, 21, 999–1009, doi:10.3762/bjoc.21.81

• incorporated into cyclization reactions. The iminium species generated from enamides via nucleophilic addition or substitution are capable of engaging in further electrophilic additions or isomerization processes. Exploiting the multiple reactivities of enamides facilitates the development of diverse

• nucleophilic addition or substitution, the resulting iminium ions often undergo direct hydrolysis, preventing further use in a cascade nucleophilic addition. As a result, enamines are not ideal partners in tandem reactions for the synthesis of nitrogen-containing products. As analogues to enamines, the

On the photoluminescence in triarylmethyl-centered mono-, di-, and multiradicals

• Daniel Straub,
• Markus Gross,
• Mona E. Arnold,
• Julia Zolg and
• Alexander J. C. Kuehne

Beilstein J. Org. Chem. 2025, 21, 964–998, doi:10.3762/bjoc.21.80

• comparison to triarylmethyl units that have been symmetry broken by the single substitution with a donor. However, simple symmetry arguments cannot explain why threefold-substituted triarylmethyl radicals have often comparable or higher ϕ than their monofunctionalized homologues. Also, the concept of

• the time that they remain in their enantiopure state. The glum as a measure for the strength of CPL is of order 8 × 10−4 for PTM and 5 × 10−4 for TTM. Mixed halide triarylmethyl radicals Substitution of all para-positions in PTM with iodine atoms yields the 3I-PTM radical with a red-shifted emission

• strong increase in ϕ; however, no further information is given to support this claim. While substitution of all para-positions with hetero-halogens or chalcogens does not induce a different symmetry in the ground state of the molecule, substitution of only one of the para-chlorines of PTM with bromine or

Silver(I) triflate-catalyzed post-Ugi synthesis of pyrazolodiazepines

• Muhammad Hasan,
• Anatoly A. Peshkov,
• Syed Anis Ali Shah,
• Andrey Belyaev,
• Chang-Keun Lim,
• Shunyi Wang and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2025, 21, 915–925, doi:10.3762/bjoc.21.74

• isocyanides, followed by a silver(I) triflate-catalyzed intramolecular heteroannulation of the resulting pyrazole-tethered propargylamides occurring in a 7-endo-dig fashion. The approach is scalable and tolerates a diverse range of substitution patterns. Keywords: heterocycles; post-MCR transformations

• carboxylic acid component 3 and additional keto-carbonyl group in aryl glyoxal 1. This approach was further advanced by Ding's group to produce a broader range of benzodiazepines with diverse substitution patterns by shuffling the necessary functional groups within the Ugi reaction components [34][35][36

• of post-Ugi transformations leading to the formation of fused seven-membered heterocycles. A series of target pyrazolodiazepines were generated through the variation of substitution patterns on all components of the Ugi reaction while several limitations of the methodology were also identified. In

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

• isomerization of alkenes [18][19], [2 + 2] cycloadditions [20][21][22][23][24], and dearomative [4 + 2] cycloadditions [25][26][27]. When considering conjugated alkenes, the triplet excited state energy and excited state lifetime are intrinsically linked to the degree of conjugation and substitution of a

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

• medicine. Despite their potential, their structural diversity is still limited and a larger pool of substitution patterns remains to be systematically investigated. This is paramount as electronic effects play a crucial role in the behavior of photoswitches and a deeper understanding enables their

• relative position of the absorption bands in the azobenzene derivatives depends on the substitution pattern on the aromatic rings, which can act as a handle to affect the absorption properties of the compound class [3]. For instance, push–pull systems or the introduction of tetra-ortho substituents were

• investigated in detail and allowed to correlate thermal relaxation rates and steric or electronic effects as well as mechanistic peculiarities, which has been in the spotlight recently for different classes of azobenzenes [34]. Despite these studies, the variety of substitution patterns in PAPs is limited

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

• ) has occurred at the exocyclic sp2-hybridized carbon atom, leading to the substitution of the 4-methoxybenzylamino group by a methylamino group. Therefore, the presence of substituents (electron-donating or electron-withdrawing groups) on the benzene rings attached to the 1- and 5-positions of the

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

• ) derivatives. Push–pull substitution on the 2 and 3 position as well as introduction of oxygen or nitrogen at position 7 of the NBD scaffold have led to the development of a new family of photoswitches. We studied the potential conversion of norbornadiene to quadricyclane (QC) isomers. As main investigation

• variations in the switching properties. However, it is important to note that altering one property typically impacts other characteristics as well [21][22]. In this regard, both the substitution of the NBD periphery to produce push–pull derivatives and the variation of the central scaffold itself have been

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)2. The final product was formed by a simple nucleophilic substitution of the phosphorus center (Scheme 20). The N–P bond formation is a critical process in organic synthesis due to the preparation of various materials with different biological and medicinal activities. In 2021 Wang et al. [65

• reaction proceeded with anodic oxidation of iodide to iodine, followed by a reaction with dialkyl phosphite to give I–P(O)(OR)2. The final product was formed by a simple nucleophilic substitution of phenols with I–P(O)(OR)2. In 2021, Wang et al. [65] presented a report on electrochemical P–O bond formation

• the rings contained electron-withdrawing groups. It is suggested that the reaction proceeded via single-electron oxidation of thiocyanate at the anode. DBU was used in the reaction for a simple nucleophilic substitution of phosphonate with a cyanide group in the formed intermediate (Scheme 28). In

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

• internal rotation in 11 via TS8 and reaction with TMSCN to give adduct 13 (see Figure 3). Distances and bond lengths are given in pm. Catalyst 7 is replaced in TS 11-12 by concerted electrophilic intramolecular substitution with formal trimethylsilyl cation as electrophile. Please note the surprisingly

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

• 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