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

• metal-free annulation reaction between electron-rich 3-aryloxetan-3-ols 142 and 1,2-diols under Brønsted acid catalysis (Scheme 51) [105]. The resulting 1,4-dioxanes 218 were obtained mostly in moderate to high yields and high regio- and diastereoselectivities were achieved with unsymmetrical diols. The

Recent advances in amidyl radical-mediated photocatalytic direct intermolecular hydrogen atom transfer

• Hao-Sen Wang,
• Lin Li,
• Xin Chen,
• Jian-Li Wu,
• Kai Sun,
• Xiao-Lan Chen,
• Ling-Bo Qu and
• Bing Yu

Beilstein J. Org. Chem. 2025, 21, 1306–1323, doi:10.3762/bjoc.21.100

• cycloalkenes and alcohols. To eliminate the need for noble metal photocatalysts in the system, Duan’s group employed 2,4,5,6-tetra-9H-carbazol-9-yl-1,3-benzenedicarbonitrile (4CzIPN) as a metal-free photocatalyst (Scheme 3) [71]. This system initiated the formation of amidyl radical 20 from HRP-3 through a

• transformation. Representative photocatalysts discussed in this review. Alkylation of C(sp3)–H catalyzed by amidyl radical under visible light. Direct heteroarylation of C(sp3)–H catalyzed by amidyl radical under visible light. Alkylation of C(sp3)–H catalyzed by amidyl radical and metal-free photocatalyst under

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

• transformations, (4) electrochemical approaches, and (5) metal-free or electron donor–acceptor (EDA)-driven systems. The substrate scope, limitations, and mechanistic aspects of these radical cascade cyclization strategies are critically examined. Review N-Arylalkenes: alkyl C(sp3)–H radicals Early investigations

• oxidant and initiator, enabling an efficient intermolecular cascade cyclization process (Scheme 5) [5]. In this strategy, a novel, selective, metal-free synthetic method was introduced for the synthesis of isoxazoline-featured oxindoles through iminoxyl radical-promoted cascade oxyalkylation

• cyclization and deprotonation to yield the desired cyclic product 40, with Umemoto’s reagent serving both as the trifluoromethyl source and the oxidant. In 2023, Li and Fu’s group reported a novel metal-free electrochemical oxidative difluoroethylation method for constructing azaheterocycles, using sodium

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

• compounds and N-acylbenzotriazole 97 (Scheme 36) [71]. In this work, the photoactive [FeCl4]− formed in situ triggered silyl radical 119 generation, leading to N-silylamine 120 as the active amine nucleophile. 2.1.4 Metal-free catalysis: Despite the wide applications of metal-based catalysts in developing O

• /N-acylation reactions, metal catalysts, particularly precious transition metals, are considered less sustainable due to their limited availability. Therefore, metal-free catalysis methods have emerged as an alternative to respond to the green chemistry agenda. For instance, Huy and Mbouhom (2019

• -abundant transition metal, Patel and Patel (2020) utilized a Ni salt of phosphomolybdic acid (NiHPMA) to synthesize methyl cinnamate (44) from cinnamaldehyde (162) via a reactive peroxo species 165 (Scheme 53) [94]. Beyond transition metals, metal-free oxidative esterifications, such as carbene-based

Harnessing tethered nitreniums for diastereoselective amino-sulfonoxylation of alkenes

• Shyam Sathyamoorthi,
• Appasaheb K. Nirpal,
• Dnyaneshwar A. Gorve and
• Steven P. Kelley

Beilstein J. Org. Chem. 2025, 21, 947–954, doi:10.3762/bjoc.21.78

• are operationally very simple and only use commercial I(III) reagents and sulfonic acids, amounting to a metal-free protocol for alkene amino-oxygenation. No special precautions need be taken to exclude air or ambient moisture, and the products are amenable to further transformations. Keywords

• : alkene; amino-sulfonoxylation; metal-free; tethered nitrenium; Introduction Our laboratory has a programmatic focus on the development of metal-free oxidation reactions that avoid the use of toxic reagents such as osmium and chromium [1][2][3]. In line with this agenda, we recently explored a mild amino

• regioselective, diastereoselective, and metal-free protocol for alkene amino-hydroxylation, which compared favorably to prior art in this area [25][26][27][28][29][30][31][32]. Naturally, we wondered if other O-nucleophiles were competent in the ring-opening of the aziridinium intermediate. Indeed, almost all

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

• -García and Fernández-Rodríguez reported on the practicality of metal-free BCl3-catalyzed borylation cyclization reactions in synthesis (Scheme 16) [45]. Biphenyl-embedded 1,3,5-trienes-7-yne compounds 58 react with BCl3 under catalyst-free and additive-free conditions to form novel polycyclic boronated

• for the time-controlled palladium-catalyzed divergent synthesis of silacycles [43]. Metal-free temperature-controlled regiodivergent borylative cyclizations of enynes [45]. Nickel-catalyzed switchable site-selective alkene hydroalkylation by temperature regulation [46]. Copper-catalyzed

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

• %). Results and Discussion Synthesis The PAPs in this study were obtained in a straightforward, three-step metal-free synthesis from commercially available aniline derivatives adapting known procedures [31][38]. An overview of the compounds used in this study and their synthesis is displayed in Scheme 1

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

• electrochemical synthesis method for the transition-metal-free cyclization and selenation/halogenation of alkynyl phosphonates at 45 °C under N2. This method can chemoselectively convert these products into halogen-functionalized cyclic enol phosphonates. The reaction is carried out in an undivided cell using

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

• performed poorly due to competitive transition-metal-free processes via α-borylcarbanion formation. The substituent of the boron atom proved equally important: neopentylglycolato groups (Bnep) outperformed pinacolato (Bpin) or propanediolato groups (Bpro) in stereoselectivity. The optimized conditions

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

• ). 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

• DMSO (Scheme 12) [45]. In this case, the reaction works well under metal-free conditions using iodine as the catalyst. Remarkably, the activation of DMSO was accomplished using Selectfluor, and in this case, DMSO is the source of a C-1 unit. It is important to note that the reaction could be performed

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

• , making it particularly suited for large-scale applications. Recent advances highlight the unique advantages of both metal-based and metal-free catalysts under red-light irradiation, broadening the range of possible reactions, from selective oxidations to complex polymerizations. In biological contexts

• that the photocatalytic efficiency of these molecules does not necessarily rely on the presence of a central metal atom. Free-base porphyrins, in particular, have demonstrated significant potential in red-light-driven transformations due to their versatile photophysical properties. These metal-free

Synthesis, characterization, and photophysical properties of novel 9‑phenyl-9-phosphafluorene oxide derivatives

• Shuxian Qiu,
• Duan Dong,
• Jiahui Li,
• Huiting Wen,
• Jinpeng Li,
• Yu Yang,
• Shengxian Zhai and
• Xingyuan Gao

Beilstein J. Org. Chem. 2024, 20, 3299–3305, doi:10.3762/bjoc.20.274

• available 2-bromo-4-fluoro-1-nitrobenzene, featuring a noble-metal-free system, mild reaction conditions, and a good yield, especially for the final Cs2CO3-facilitated nucleophilic substitution (77–91% yield). The characterization data obtained from IR and NMR spectroscopy (1H, 13C, 19F, and 31P) as well as

• studies, revealing that their photophysical behavior can be affected by the different substituents in the donor carbazole group. Keywords: carbazole; D−A−D type; noble-metal-free system; 9‑phenyl-9-phosphafluorene oxide; photophysical properties; Introduction π-Conjugated molecular materials containing

• , starting from commercially available 2-bromo-4-fluoro-1-nitrobenzene under noble-metal-free conditions. The structures and photophysical properties of the desired molecules were also determined. Results and Discussion Synthesis and structural characterization The synthesis of the PhFlOP-based compounds 7

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

• building blocks like organohalides can be converted into alkyl radicals by means of photoinduced silane-mediated halogen-atom transfer (XAT) to offer a mild and straightforward methodology of alkylation. In this research, we present a metal-free strategy for the photochemical alkylation of dehydroalanine

•  3), obtaining a slightly elevated yield (67%) compared to compound 3, which was previously formed at a 0.5 mmol scale. Conclusion In conclusion, a photochemical methodology to promote the metal-free alkylation of dehydroalanine derivatives was developed, by means of silane-mediated alkyl bromide

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

• carbocycles can be synthesized mildly and effectively using HVI reagents. Nitrogen nucleophiles A metal-free synthesis of β-fluorinated piperidines was reported in 2012 by Meng, Li and co-workers (Scheme 1) [26]. The authors describe a reaction using PhI(OPiv)2 as oxidant with HF·pyridine as the source of

• and co-workers reported a mild, metal free-synthesis of fluorobenzoxazepines 30 in 2016 (Scheme 13) [37]. Using 1-fluoro-3,3-dimethylbenziodoxole (12) and 4 Å molecular sieves, a range of benzamides 29 were successfully cyclised in good yields. The sustainability of the reaction was improved by

• with subsequent nucleophilic attack by chloride to form the product. A metal-free chlorocyclisation of indole derivatives was reported by Yu and co-workers in 2019 (Scheme 25) [45]. The authors reported the use of 1-chloro-1,2-benziodoxol-3-one (45) as a single reagent to form 6- or 7-membered rings

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

• Mandeep K. Chahal School of Chemistry and Forensic Science, University of Kent, Canterbury, CT2 7NH, UK 10.3762/bjoc.20.257 Abstract This review provides an overview of recent progress made in the field of catalysis using metal-free tetrapyrrolic macrocycles, focusing on calix[4]pyrroles

• applied in various fields, including organometallic catalysis, dye-sensitized solar cells, sensing, artificial olfactory systems, photodynamic therapy (PDT), anticancer drugs, biochemical probes, and electrochemical devices. Relevant examples of these two pyrrolic macrocycles as metal-free organocatalysts

• two macrocycles as metal-free catalysts. Keywords: calix[4]pyrroles; electrocatalysis; free-base porphyrins; organocatalysis; photocatalysis; tetrapyrrolic macrocycles; Introduction Tetrapyrrolic macrocycles are a class of cyclic compounds that contain four pyrrolic units in their ring. Examples of

Advances in radical peroxidation with hydroperoxides

• Oleg V. Bityukov,
• Pavel Yu. Serdyuchenko,
• Andrey S. Kirillov,
• Gennady I. Nikishin,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2024, 20, 2959–3006, doi:10.3762/bjoc.20.249

• peroxidation of 31 with the formation of products 32 can be achieved as both using Cu-catalysis and in metal-free conditions (Scheme 13). The metal-free peroxidation with TBHP was also demonstrated using 3,4-dihydro-1,4-benzoxazin-2-ones 33 as substrates (Scheme 13) [54]. The assumed mechanism of the target

• product 32 formation is similar to the metal-catalyzed peroxidation described in Scheme 12 in the case of using the Cu(II)/TBHP oxidation system. Under metal-free conditions the tert-butoxy radical A is probably formed via homolytic thermal decomposition of TBHP. Recently, the electrochemical generation

• in situ-generated Cu(I) complexes was developed (Scheme 23) [43]. 2-Phenylbutane (64) was converted into peroxide 65 in a 70% yield with 4% ee. A visible light-induced direct decarboxylative peroxidation of carboxylic acids 66 with the formation of peroxides 67 under metal-free conditions using Mes

Synthesis of fluorinated acid-functionalized, electron-rich nickel porphyrins

• Mike Brockmann,
• Jonas Lobbel,
• Lara Unterriker and
• Rainer Herges

Beilstein J. Org. Chem. 2024, 20, 2954–2958, doi:10.3762/bjoc.20.248

• Williamson ether synthesis to yield 22 (78%), 23 (44%), and 24 (44%). Compounds 22, 23, and 24 were used as aldehyde components in the Rothemund-type synthesis of metal-free porphyrins 26 (9%), 27 (18%), and 28 (21%) (see Scheme 3). Metalation was achieved with nickel acetylacetonate to obtain the ester

• ester-functionalized aldehydes 22, 23, and 24. Conditions: a) NIS, TFA, Na2CO3, MeCN, reflux, 18 h; b) Cu2O·H2O, 2-pyridinaldoxime, TBAB, CsOH, H2O, N2, rt, 18 h; c) Cs2CO3, DMAc, N2, rt, 3 h. Porphyrin synthesis. a) Rothemund porphyrin synthesis of metal-free porphyrins 26, 27, and 28; b) metalation of

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

• Ritu Mamgain,
• Kokila Sakthivel and
• Fateh V. Singh

Beilstein J. Org. Chem. 2024, 20, 2891–2920, doi:10.3762/bjoc.20.243

• unsymmetrical forms of these salts serve as effective electrophilic arylating reagents in various organic syntheses. The use of diaryliodoniums in C–C and carbon–heteroatom bond formations, particularly under metal-free conditions, has further enhanced the popularity of these reagents. In this review, we

• concentrate on various arylation reactions involving carbon and other heteroatoms, encompassing rearrangement reactions in the absence of any metal catalyst, and summarize advancements made in the last five years. Keywords: arylation reaction; diaryliodonium salts; electrophilic arylation reagent; metal-free

• five to seven-membered cyclic compounds [47]. Arylation reactions using diaryliodonium salts can occur through four distinct mechanisms. First, the arylation can occur under metal-free conditions, involving the formation of a three-membered ring transition state through ligand coupling, leading to the

Transition-metal-free decarbonylation–oxidation of 3-arylbenzofuran-2(3H)-ones: access to 2-hydroxybenzophenones

• Bhaskar B. Dhotare,
• Seema V. Kanojia,
• Chahna K. Sakhiya,
• Amey Wadawale and
• Dibakar Goswami

Beilstein J. Org. Chem. 2024, 20, 2655–2667, doi:10.3762/bjoc.20.223

• , Trombay, Mumbai-400085, India Homi Bhabha National Institute, Anushaktinagar, Mumbai, PIN-400094, India 10.3762/bjoc.20.223 Abstract A transition-metal-free decarbonylation–oxidation protocol for the conversion of 3-arylbenzofuran-2(3H)-ones to 2-hydroxybenzophenones under mild conditions has been

• abilities has been verified by mathematical calculations. Keywords: decarbonylation–oxidation; hydroperoxide; 2-hydroxybenzophenone; transition-metal-free; UV-protection; Introduction Benzophenone compounds are ubiquitous in nature, and show biological activities such as anti-inflammatory, antiviral, and

• environmental hazards, and this can only be circumvented using a transition-metal-free synthesis protocol. Although eco-friendly methods for the synthesis of 2-hydroxybenzophenones have been reported via a cycloaromatization of α-alkenoyl ketene dithioacetals and nitroethane in water [15], an alternate and more

Transition-metal-free synthesis of arylboronates via thermal generation of aryl radicals from triarylbismuthines in air

• Yuki Yamamoto,
• Yuki Konakazawa,
• Kohsuke Fujiwara and
• Akiya Ogawa

Beilstein J. Org. Chem. 2024, 20, 2577–2584, doi:10.3762/bjoc.20.216

• under transition-metal-free and open-air conditions. Conventional methods required photoirradiation or electrolysis to generate aryl radicals from triarylbismuthines. In this study, it was found that simply heating the solution of triarylbismuthines in benzotrifluoride (BTF) in air successfully led to

• the generation of aryl radicals, and the subsequent reaction with bis(pinacolato)diboron afforded a variety of arylboronates in moderate to good yields. Keywords: arylboronates; bis(pinacolato)diboron; radical reactions; transition-metal-free synthesis; triarylbismuthines; Introduction Arylboronates

• , the development of new synthetic methods of arylboronates using stable and versatile reagents under transition-metal-free conditions has recently attracted much attention [23][24][25][26][27]. In particular, the use of radical reactions has been considered as one of the effective methods, since

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• product (Scheme 15). The synthesis of aziridines can be achieved via the formation of nitrenes in either a metal-catalyzed or metal-free fashion. In this context, Wickens and colleagues presented a remarkable dication pool strategy for accessing N-alkylaziridines via metastable dicationic intermediates

• was demonstrated by the LSF of primary natural and pharmaceutical amines carrying potential competing nucleophiles, such as tryptamine and primaquine (Scheme 16). In the context of electrochemical difunctionalizations the Lei group published a transition-metal-free electrochemical difunctionalization

• − is protonated to produce DDQH2. The anodic oxidation of DDQH2 regenerates DDQ, which re-enters the catalytic cycle (Scheme 29). Furthermore, Qiu and coworkers disclosed a metal-free electrochemical dihydroxylation of unactivated alkenes using water as the hydroxy source under air conditions [40

HFIP as a versatile solvent in resorcin[n]arene synthesis

• Hormoz Khosravi,
• Valeria Stevens and
• Raúl Hernández Sánchez

Beilstein J. Org. Chem. 2024, 20, 2469–2475, doi:10.3762/bjoc.20.211

• showed resorcinol in the reaction mixture. This observation led us to run a control experiment in the absence of aldehyde, which showed that HFIP leads to metal-free deiodination of 2-iodoresorcinol (Figure 1a). Finally, while all new compounds reported herein have full spectroscopic characterization

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• essential to provide a comprehensive overview of this significant topic. Review Asymmetric allylation with boron-based reagents The research on the metal-free, asymmetric organocatalytic allylation of acylimines was pioneered in 2007 by Schaus and co-workers [24]. In their elegant approach, high

• transfer reagents; (iv) direct metal-free imine carbanion addition to electrophilic alkene. Class (i) underwent an evolution from catalysis by covalent interaction to chiral hydrogen-bonded catalysis, which allowed the expansion of the allyl component scope from simple allyl to substituted allyl groups

• apparent from the presented work, that metal-free organocatalytic nucleophilic asymmetric allylations of ketimines remains a significant challenge for all four general classes of allylation, the solution of which is likely to be revealed in the forthcoming research. Two different pathways for the Hosomi

Hydrogen-bond activation enables aziridination of unactivated olefins with simple iminoiodinanes

• Phong Thai,
• Lauv Patel,
• Diyasha Manna and
• David C. Powers

Beilstein J. Org. Chem. 2024, 20, 2305–2312, doi:10.3762/bjoc.20.197

• iminoiodinanes for the metal-free aziridination of unactivated olefins. 1H NMR and cyclic voltammetry (CV) studies indicate that hydrogen-bonding between HFIP and the iminoiodinane generates an oxidant capable of direct NGT to unactivated olefins. Stereochemical scrambling during aziridination of 1,2

• recently developed a metal-free aziridination of unactivated olefins via the intermediacy of an N-pyridinium iminoiodinane (Scheme 1b) [34]. We rationalized the enhanced reactivity towards olefin aziridination as a result of charge-enhanced iodine-centered electrophilicity arising from the cationic N

• frequently encountered iminoiodinanes in NGT catalysis (Scheme 1c). This simple procedure afforded the formal transfer of various nitrogen groups, including those derived from complex amines, and is complementary to other metal-free aziridinations of unactivated olefins [35][36][37][38][39]. Results and

Metal-free double azide addition to strained alkynes of an octadehydrodibenzo[12]annulene derivative with electron-withdrawing substituents

• Naoki Takeda,
• Shuichi Akasaka,
• Susumu Kawauchi and
• Tsuyoshi Michinobu

Beilstein J. Org. Chem. 2024, 20, 2234–2241, doi:10.3762/bjoc.20.191

• azide–alkyne cycloaddition; Introduction The strain-promoted azide–alkyne cycloaddition (SpAAC) is one of the most representative metal-free click chemistry reactions [1][2][3][4][5]. SpAAC has been mainly employed in bioconjugation in the fields of chemical biology and medicinal chemistry due to its

• oxidation-controlled cyclooctyne-1,2-quinone cycloaddition (SPOCQ) was developed and employed in the same fields of chemical biology [6][7]. On the other hand, the use of the SpAAC in materials science was slow. We developed another class of metal-free click chemistry reactions, such as the [2 + 2

• metal-free click reaction was employed to crosslink a partially azidated poly(vinyl chloride). The crosslinking proceeded by simply mixing the polymer and crosslinker in THF and evaporating, and the formation of the crosslinked polymer film was confirmed by the strain–stress curves. The developed method