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

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

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

• ,d, respectively, as the expected reactive intermediates after N2 elimination from 2c and 2d. Trapping of transient thiocarbonyl S-methanides 1 with enolizable 1-substituted 5-mercapto-1H-tetrazoles 4 Adamantanethione S-methanide (1a) is considered as a prominent representative of the ‘sulfur

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

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

• ) employed N-formylpyrrolidine (FPyr) and trichlorotriazine (TCT) to catalyze the amidation of cinnamic acid derivative 121. The reaction proceeds via formation of the reactive acid chloride 36 through cascade reaction involving reactive intermediates 123 and 124 (Scheme 37) [72]. Zeng and co-workers (2019

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

• the critical role of reaction medium polarity in modulating reactive intermediates, offering a strategic lever to toggle between C–H functionalization and reductive manifolds in photochemical transformations. In 2024, the Cheng group developed a palladium/chiral norbornene (NBE)-catalyzed cyclization

• reaction pathways, selectivity, and catalytic efficiency. By exploiting dynamic acid–base equilibria or stimuli-responsive systems, chemists can manipulate substrate activation, stabilize reactive intermediates, and orchestrate complex multistep transformations under mild conditions [47]. In 2016, Lu's

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

• thus to have a better control of the selectivity and the DAR, leading to more homogeneous ADCs. In this specific context, photocatalysis (Figure 2) enables site-specific bioconjugation by generating reactive intermediates (such as radicals or electron-deficient species) that can selectively react under

• emerged as a transformative approach in the modification of proteins, enabling researchers to achieve selective and efficient conjugation under mild conditions [37]. By utilizing visible light and transition-metal catalysts, this technique allows the generation of reactive intermediates that can

• , storage and handling of conjugated antibodies require special attention to minimize exposure to ambient light, which could contribute to structural instability and promote aggregation over time. Reaction time: Proteins and antibodies are delicate macromolecules, and prolonged exposure to light or reactive

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

• generate crotonic condensation adducts of active methylene compounds and formaldehyde at room temperature in the absence of strong acids and bases. The formed adducts were highly reactive intermediates capable of reacting with dienes in a three-component reaction, leading to the formation of Diels–Alder

• under the above conditions to form highly reactive intermediates capable of [4 + 2]-cycloaddition reactions. Cyclopentadiene, cyclohexadiene, 2,3-dimethylbutadiene and isoprene were used as traps for the intermediates formed. The results are presented in Scheme 3. In general, the reactions produced

• formaldehyde at room temperature in the absence of strong acids and bases. These adducts are highly reactive intermediates capable of reacting with dienes in three-component reactions, leading to the formation of Diels–Alder main products or hetero-Diels–Alder adducts. In some cases, Michael addition products

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

• methodologies for carbon–carbon and carbon–heteroatom bond formation. These advances have been accomplished by recognizing electrochemistry as an effective and sustainable approach for electron transfer processes to enable the generation of highly reactive intermediates. Additionally, the rapid growth of dual

Mechanochemical difluoromethylations of ketones

• Jinbo Ke,
• Pit van Bonn and
• Carsten Bolm

Beilstein J. Org. Chem. 2024, 20, 2799–2805, doi:10.3762/bjoc.20.235

• through the formation of novel reactive intermediates [15][16][17][18]. Fluorine-containing functional groups are essential structural motifs in the development of new bioactive compounds and functional materials. Compared to their non-fluorinated analogs, the presence of fluorine atoms in molecular

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• using an enzyme or at what stage in a synthesis the enzyme is employed: 1) regio- and stereoselective late-stage functionalization of core scaffolds, 2) in situ generation of highly reactive intermediates, and 3) the one-step construction of macrocyclic or fused multicyclic scaffolds via regio- and

• brassicicenes 27–29. In situ generation of highly reactive intermediates: trichodimerol and the bisorbicillinoid family The bisorbicillinoid family, isolated from fungi such as Penicillium chrysogenum, has dimeric intricate scaffolds, as exemplified by trichodimerol (2) (Scheme 4) [28][29]. The biosynthetic

• categorized into three distinct classifications based on the type of enzymatic conversions: 1) regio- and stereoselective late-stage functionalization of core scaffolds, 2) in situ generation of highly reactive intermediates, and 3) one-step construction of macrocyclic or fused multicyclic scaffolds. This

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• -fluorobenzoates as both photocatalysts or photo-auxiliaries and was demonstrated on a number of benzylic examples. Photochemical Photochemical methods have proven to be powerful tools in the generation of reactive intermediates, including benzylic radicals [64][65][66][67]. Oxidative photochemical

• fluorination of primary benzylic substrates is a highly challenging reaction, due to the lower stability of the reactive intermediates involved in the mechanism. This is reflected in the fact that very few papers have been reported beyond the work on methylquinolines by the Sanford group (Figure 30), and a few

Generation of alkyl and acyl radicals by visible-light photoredox catalysis: direct activation of C–O bonds in organic transformations

• Mithu Roy,
• Bitan Sardar,
• Itu Mallick and
• Dipankar Srimani

Beilstein J. Org. Chem. 2024, 20, 1348–1375, doi:10.3762/bjoc.20.119

• catalysis In recent times, visible-light-mediated photoredox chemistry has evolved as a unique tool for various organic transformations. In contrast to traditional catalysis, the photochemical process uses an electron or energy transfer mechanism to form reactive intermediates. Typically, a photocatalyst is

Photoinduced in situ generation of DNA-targeting ligands: DNA-binding and DNA-photodamaging properties of benzo[c]quinolizinium ions

• Julika Schlosser,
• Olga Fedorova,
• Yuri Fedorov and
• Heiko Ihmels

Beilstein J. Org. Chem. 2024, 20, 101–117, doi:10.3762/bjoc.20.11

• cancer [39], and bacterial, fungal, parasitic and viral infections [40][41]. In general, PDT operates on the basis of a photosensitizer, which generates reactive intermediates upon irradiation [42][43][44][45]. Hence, in the type-I mechanism the photosensitizer induces the formation of reactive oxygen

• of intermediate hydroxyl radicals and C-centered radicals. Singlet oxygen, one of the most important reactive intermediates in conventional PDT, however, only contributes to marginal extent to the DNA damage. Therefore, these results are a promising starting point for the development of novel

• ]quinolizinium 3f revealed a more complex mechanistic scenario (Scheme 4). While it became clear that the irradiation of this substrate in the presence of DNA leads to efficient DNA-strand cleavage, the systematic assessment of parameters that influence this reaction revealed the formation of different reactive

Beyond n-dopants for organic semiconductors: use of bibenzo[d]imidazoles in UV-promoted dehalogenation reactions of organic halides

• Kan Tang,
• Megan R. Brown,
• Chad Risko,
• Melissa K. Gish,
• Garry Rumbles,
• Phuc H. Pham,
• Oana R. Luca,
• Stephen Barlow and
• Seth R. Marder

Beilstein J. Org. Chem. 2023, 19, 1912–1922, doi:10.3762/bjoc.19.142

• ) that simple one- or two-electron donors capable of exergonic ground-state electron transfer to these substrates will be rather air sensitive, complicating their handling and use. In addition some molecular reductants can themselves react with the reactive intermediates; for example, the dehalogenation

Anion–π catalysis on carbon allotropes

• M. Ángeles Gutiérrez López,
• Mei-Ling Tan,
• Giacomo Renno,
• Augustina Jozeliūnaitė,
• J. Jonathan Nué-Martinez,
• Javier Lopez-Andarias,
• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2023, 19, 1881–1894, doi:10.3762/bjoc.19.140

• deprotonate the substrate 4 and produce the conjugate bases I and II as the first reactive intermediates directly on the active π surface (Figure 2 and Figure 7) [80]. Calibrated against triethylamine 23, fullerene dimer 37 catalyzed enolate addition with an A/D37/23 = 12.5. This is more than twice the A/D22

• electrophile. To accelerate and direct this charge displacement, any electron-rich motif in transition states and reactive intermediates should be stabilizable by induced anion–π interactions with MWCNTs that are polarized by an electric field. Inversion of the applied voltage should allow to stabilize the

• fullerenes as well. The unique polarizability of fullerene monomers like 1 is thought to induce strong anion–π interactions and thus account for the observed catalytic activity (Figure 7A) [12]. This polarizability should further increase in fullerene dimers like 36 [80]. Anions, anionic reactive

Cyclization of 1-aryl-4,4,4-trichlorobut-2-en-1-ones into 3-trichloromethylindan-1-ones in triflic acid

• Vladislav A. Sokolov,
• Andrei A. Golushko,
• Irina A. Boyarskaya and
• Aleksander V. Vasilyev

Beilstein J. Org. Chem. 2023, 19, 1460–1470, doi:10.3762/bjoc.19.105

• -enones) undergo intramolecular transformation into 3-trichloromethylindan-1-ones (CCl3-indanones) in Brønsted superacid CF3SO3H (triflic acid, TfOH) at 80 °C within 2–10 h in yields up to 92%. Protonation of the carbonyl oxygen of the starting CCl3-enones by TfOH affords the key reactive intermediates

• that the formation of dications D does not take place. Species B should be the key reactive intermediates that undergo cyclization into indanones 3 with a negative Gibbs energy of −7 kJ/mol for the reaction Ba→3a. According to the calculations, the subsequent complete protonation of the hydroxy group

Radical ligand transfer: a general strategy for radical functionalization

• David T. Nemoto Jr,
• Kang-Jie Bian,
• Shih-Chieh Kao and
• Julian G. West

Beilstein J. Org. Chem. 2023, 19, 1225–1233, doi:10.3762/bjoc.19.90

• challenging-to-generate “uncontrollable” species prone to side reactions to versatile reactive intermediates enabling construction of myriad C–C and C–X bonds. This maturation of free radical chemistry has been enabled by several advances, including the proliferation of efficient radical generation methods

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

• generation of reactive intermediates for both oxidative and reductive processes via photon activation of a catalyst. Although this represents a significant step towards chemoselective and, more generally, sustainable chemistry, its efficacy is limited by the energy of visible light photons. Nowadays

• magnitude potentials can lead to uncontrolled reactions due to the accumulation of reactive intermediates within proximity of the electrode surface. Compared to homogeneous photocatalytic processes that lend themselves to high selectivity for taming radical intermediates by taking place in bulk solution

• radicals that often provide access to new dimensions of synthetic chemical space, the field of single electron transfer (SET) in organic synthesis has expanded considerably in the past two decades. Among this area, photoredox catalysis (PRC) is highly attractive due to its abilities i) to generate reactive

Asymmetric tandem conjugate addition and reaction with carbocations on acylimidazole Michael acceptors

• Brigita Mudráková,
• Renata Marcia de Figueiredo,
• Jean-Marc Campagne and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 881–888, doi:10.3762/bjoc.19.65

• introduce synthetically valuable functionalities. In this way, a range of acylimidazoles featuring cycloheptatrienyl, benzodithiolyl, ferrocenyl, and chromenyl substituents were prepared. The DFT calculated HOMO energies and NBO charges of the intermediate zinc enolates allowed placement of these reactive

• intermediates among other metal enolates obtained in conjugate additions. Experimental General procedure for the one-pot conjugate addition of organozinc reagents to acylimidazole followed by trapping with carbocations: In a flame-dried Schlenk flask flushed with Ar, Cu(OTf)2 (1.81 mg, 0.005 mmol, 2 mol %) and

Direct C2–H alkylation of indoles driven by the photochemical activity of halogen-bonded complexes

• Martina Mamone,
• Giuseppe Gentile,
• Jacopo Dosso,
• Maurizio Prato and
• Giacomo Filippini

Beilstein J. Org. Chem. 2023, 19, 575–581, doi:10.3762/bjoc.19.42

• -electron-transfer (BET), a suitable leaving group (LG) needs to be included in one of the precursors. In this manner, reactive intermediates (e.g., radical species) may be generated in solution through the irreversible fragmentation of the substrates [15][21][22]. These intermediates eventually react to

Group 13 exchange and transborylation in catalysis

• Dominic R. Willcox and
• Stephen P. Thomas

Beilstein J. Org. Chem. 2023, 19, 325–348, doi:10.3762/bjoc.19.28

• transborylation in catalysis (Scheme 6) [69]. Reactive intermediates were characterised and BH3 was observed to be generated in situ by the decomposition of HBpin. The proposed catalytic cycle involved nucleophile-promoted decomposition of HBpin to various borohydride species 19, which reacted with the BH3

Synthesis and reactivity of azole-based iodazinium salts

• Thomas J. Kuczmera,
• Annalena Dietz,
• Andreas Boelke and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2023, 19, 317–324, doi:10.3762/bjoc.19.27

• compounds based on azol-based iodazinium as reactive intermediates. Most interestingly, functionalization of the heteroarene salts was achieved without an undesired attack of the delicate C–I bond at the hypervalent iodine center. Experimental General procedure for the synthesis of azoiodazinium salts

Inline purification in continuous flow synthesis – opportunities and challenges

• Jorge García-Lacuna and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 1720–1740, doi:10.3762/bjoc.18.182

• , which also improves safety issues as it traps toxic and explosive reactive intermediates (Scheme 7) [76]. Additional studies include a 3-step reaction to form triazoles in good yields [77], and the synthesis of the bisoxazole natural product siphonazole A using immobilized species [78]. The use of real

Radical cation Diels–Alder reactions of arylidene cycloalkanes

• Kaii Nakayama,
• Hidehiro Kamiya and
• Yohei Okada

Beilstein J. Org. Chem. 2022, 18, 1100–1106, doi:10.3762/bjoc.18.112

• ; spiro ring system; Introduction Single-electron transfer is one of the simplest modes for small molecule activation, employing a polarity inversion to generate radical ions which have proven to be unique reactive intermediates in the field of synthetic organic chemistry. A radical cation Diels–Alder

Complementarity of solution and solid state mechanochemical reaction conditions demonstrated by 1,2-debromination of tricyclic imides

• Petar Štrbac and
• Davor Margetić

Beilstein J. Org. Chem. 2022, 18, 746–753, doi:10.3762/bjoc.18.75

• polycyclic molecules given in Figure 1 are interesting reactive intermediates which could be applied in the Diels−Alder reactions of less reactive or thermally susceptible dienes. Often, these are generated in situ and trapped with dienes in a single pot, such as 7-oxanorbornadiene imides 1–3. For instance

A study of the photochemical behavior of terarylenes containing allomaltol and pyrazole fragments

• Constantine V. Milyutin,
• Andrey N. Komogortsev,
• Boris V. Lichitsky and
• Valeriya G. Melekhina

Beilstein J. Org. Chem. 2022, 18, 588–596, doi:10.3762/bjoc.18.61

• -induced processes are of considerable interest in the context of green chemistry [8][9]. At the same time in some cases UV irradiation of organic compounds leads to the formation of highly reactive intermediates. Such objects may, possessing a specific reactivity, which define their further application in