Enantioselective radical chemistry: a bright future ahead

• Anna C. Renner,
• Sagar S. Thorat,
• Hariharaputhiran Subramanian and
• Mukund P. Sibi

Beilstein J. Org. Chem. 2025, 21, 2283–2296, doi:10.3762/bjoc.21.174

• enantioselectivities. A radical chaperone methodology is based on a multicatalytic system in which a chiral Cu(I) catalyst, Brønsted acid (camphoric acid) and Ir photocatalyst work synergistically. An asymmetric synthetic method based on radical C–H functionalization was reported by Nagib and co-workers for the

• aldolase, a photoredox catalyst, and an oxidizing agent. With this catalytic system, they were able to accomplish the C–H functionalization of glycine and α-branched amino acids, obtaining α-tri- and tetrasubstituted amino acids with moderate to good yields, good diastereoselectivity, and high

• functionalization of the terminal carbon atom of the silyl polyenolate. In the reaction of silyl tetraenol ether 47, selective reaction at the η position occurred, and the product 48 was obtained in 78% yield and 96% ee. Conclusion This perspective highlights important contributions in the area of enantioselective

Pathway economy in cyclization of 1,n-enynes

• Hezhen Han,
• Wenjie Mao,
• Bin Lin,
• Maosheng Cheng,
• Lu Yang and
• Yongxiang Liu

Beilstein J. Org. Chem. 2025, 21, 2260–2282, doi:10.3762/bjoc.21.173

• synthetic intermediates, and used to successfully modify diverse bioactive scaffolds via late-stage functionalization, collectively demonstrating the method’s synthetic utility. In 2025, the Das group developed a palladium-catalyzed cycloisomerization of 2-alkynylbenzoate-cyclohexadienone that enables

• toward bicyclo[4.3.0]nonane frameworks via geminal carbo-functionalization of 3-siloxy-1,3-dien-7-ynes (Scheme 21) [32]. A stereoselective sequence initiated by 5-exo-dig cyclization and Michael addition under cationic gold catalysis to generate strained bicyclic gold-carbene complex 101, which was

Pd-catalyzed dehydrogenative arylation of arylhydrazines to access non-symmetric azobenzenes, including tetra-ortho derivatives

• Loris Geminiani,
• Kathrin Junge,
• Matthias Beller and
• Jean-François Soulé

Beilstein J. Org. Chem. 2025, 21, 2234–2242, doi:10.3762/bjoc.21.170

• nitro (3j, 35%), as well as electron-donating groups such as methoxy (3d, 77%), dimethylamino (3k 55%) , and thiomethoxy (3l, 71%). Moreover, the reaction tolerated C–F (3f, 86%) and C–Cl (3g, 66%) bonds, enabling orthogonal functionalization. It should be noted that, as a general trend – and in

Electrochemical cyclization of alkynes to construct five-membered nitrogen-heterocyclic rings

• Lifen Peng,
• Ting Wang,
• Zhiwen Yuan,
• Bin Li,
• Zilong Tang,
• Xirong Liu,
• Hui Li,
• Guofang Jiang,
• Chunling Zeng,
• Henry N. C. Wong and
• Xiao-Shui Peng

Beilstein J. Org. Chem. 2025, 21, 2173–2201, doi:10.3762/bjoc.21.166

• synthesis of cyclic compounds have emerged. The electrochemical functionalization of alkynes was highlighted by Ahmed in 2019 [109], Zhang described radical annulation of 1,n-enynes under photo/electrochemical reaction conditions in 2023 [110], the electrochemical formation of heterocycles was summarized by

The application of desymmetric enantioselective reduction of cyclic 1,3-dicarbonyl compounds in the total synthesis of terpenoid and alkaloid natural products

• Dong-Xing Tan and
• Fu-She Han

Beilstein J. Org. Chem. 2025, 21, 2085–2102, doi:10.3762/bjoc.21.164

• decyanation [75] and double bond migration of 95 produced common intermediate 96, which was elaborated to ketone 97 [69] via four functional group manipulations, thereby achieving the formal total synthesis of (−)-conidiogenone B (17). On the other hand, functionalization and derivatization were performed on

Discovery of cytotoxic indolo[1,2-c]quinazoline derivatives through scaffold-based design

• Daniil V. Khabarov,
• Valeria A. Litvinova,
• Lyubov G. Dezhenkova,
• Dmitry N. Kaluzhny,
• Alexander S. Tikhomirov and
• Andrey E. Shchekotikhin

Beilstein J. Org. Chem. 2025, 21, 2062–2071, doi:10.3762/bjoc.21.161

• methodologies from traditional acylation/carbamoylation [9] to advanced Pd- or Rh-catalyzed C–H activation [10][11], FeIII–CuII/p-TSA–CuI catalyzed ring expansion/cyclization [12], electrochemical C–H/N–H functionalization [13], RhIII-catalyzed C–H amidation [14], etc. In contrast to chemical studies, a

• reports that focused on natural alkaloids or limited antimicrobial studies, this study expands the pharmacological scope by demonstrating selective antiproliferative effects and identifying promising SAR trends. The originality of the research lies in linking strategic scaffold functionalization

• )-one scaffold 1 was synthesized according to the optimized protocol developed by Bergman et al. [9]. Position 12 of indolo[1,2-c]quinazolin-6(5H)-one (1) (Scheme 1) corresponded to of the indole C3 position, which is typically used as a nucleophilic center for functionalization via reactions with

Bioinspired total syntheses of natural products: a personal adventure

• Zhengyi Qin,
• Yuting Yang,
• Nuran Yan,
• Xinyu Liang,
• Zhiyu Zhang,
• Yaxuan Duan,
• Huilin Li and
• Xuegong She

Beilstein J. Org. Chem. 2025, 21, 2048–2061, doi:10.3762/bjoc.21.160

• reported. A bioinspired approach represents many advantages to bring benefits to total synthesis. It could rapidly achieve complexity of the target molecule from a much simpler precursor in diverse forms of transformations such as cascade reaction, cycloaddition, and C–H functionalization, thereby, shorten

• functionalities in a complex framework are formidable challenges for mankind since such transformations in nature are precisely induced by enzymes. Bioinspired functionalization of C–H bond in total synthesis is rarely developed and it represents another challenge, despite numerous methodologies have been

Enantioselective desymmetrization strategy of prochiral 1,3-diols in natural product synthesis

• Lihua Wei,
• Rui Yang,
• Zhifeng Shi and
• Zhiqiang Ma

Beilstein J. Org. Chem. 2025, 21, 1932–1963, doi:10.3762/bjoc.21.151

• functionalization of one hydroxy group, offers beneficial procedures for accessing diverse structural motifs. In this review, we highlight a curated compilation of publications, focusing on the applications of enantioselective desymmetrization of prochiral 1,3-diols in the synthesis of natural products and

• enantioselective manner) can be utilized for a series of transformations, including functionalization, chain elongation, ring formation, etc. Therefore, the enantioselective desymmetrization of diols has drawn considerable interest among synthetic chemists. Several comprehensive reviews [14][15][16][17][18] on the

Systematic pore lipophilization to enhance the efficiency of an amine-based MOF catalyst in the solvent-free Knoevenagel reaction

• Pricilla Matseketsa,
• Margret Kumbirayi Ruwimbo Pagare and
• Tendai Gadzikwa

Beilstein J. Org. Chem. 2025, 21, 1854–1863, doi:10.3762/bjoc.21.144

• groups. This selective functionalization yielded MOFs in which the catalytically active amines are confined within highly lipophilic pores, reminiscent of many enzyme active sites. We determined that systematically increasing the lipophilicity of the pores results in a commensurate increase of catalyst

• at the hydroxy. To prevent excessive reaction at the amine, both reactions were stopped at 2 hours. Aside from 1H NMR, the independent functionalization of KSU-1 with isocyanates was also confirmed by conducting electrospray ionization mass spectrometry (ESI–MS) on samples of the MOF products

• ). Powder X-ray diffraction (PXRD) confirmed that crystallinity was preserved even after complete functionalization of DPG (Figure S8, Supporting Information File 1). To test the catalytic behavior of our amine-based lipophilic MOF catalysts, we chose the Knoevenagel condensation between benzaldehyde and

Fe-catalyzed efficient synthesis of 2,4- and 4-substituted quinolines via C(sp²)–C(sp²) bond scission of styrenes

• Prafull A. Jagtap,
• Manish M. Petkar,
• Vaishnavi R. Sawant and
• Bhalchandra M. Bhanage

Beilstein J. Org. Chem. 2025, 21, 1799–1807, doi:10.3762/bjoc.21.142

• production of approximately 30 million tons annually [40]. Their low cost and widespread availability make them highly valuable as fundamental building blocks in organic synthesis. Over the past few decades, the direct functionalization of styrenes has emerged as a prominent research area due to its

Research progress on calixarene/pillararene-based controlled drug release systems

• Liu-Huan Yi,
• Jian Qin,
• Si-Ran Lu,
• Liu-Pan Yang,
• Li-Li Wang and
• Huan Yao

Beilstein J. Org. Chem. 2025, 21, 1757–1785, doi:10.3762/bjoc.21.139

• solubility of drugs. The modified CAs encapsulate drug molecules within the host through host–guest interactions. The interactions between the drug and the calixarene enhance the solubility of the drug [60]. Further functionalization of these CAs' upper and lower rims with diverse moieties (e.g., amides

• cyclodextrins in terms of controllable functionalization [61]. In clinical applications, particularly for anticancer drug conjugation, CAs demonstrate remarkable cancer cell selectivity, minimized off-target effects, enhanced delivery efficiency, and reduced systemic toxicity. Additionally, their synthetic

3,3'-Linked BINOL macrocycles: optimized synthesis of crown ethers featuring one or two BINOL units

• Somayyeh Kheirjou,
• Jan Riebe,
• Maike Thiele,
• Christoph Wölper and
• Jochen Niemeyer

Beilstein J. Org. Chem. 2025, 21, 1719–1729, doi:10.3762/bjoc.21.134

• ) [41][42][43] have been used for attaching the crown ether macrocycle, although this strategy has the advantage that the 2,2'-hydroxy groups remain intact and can be used for further binding or functionalization. Our group recently became interested in synthesizing BINOL derivatives featuring

Azide–alkyne cycloaddition (click) reaction in biomass-derived solvent Cyrene^TM under one-pot conditions

• Zoltán Medgyesi and
• László T. Mika

Beilstein J. Org. Chem. 2025, 21, 1544–1551, doi:10.3762/bjoc.21.117

• –carbon double bond in a certain molecular structure could allow for efficient subsequent functionalization via, for example, an addition reaction, opening possibilities for building even more complex molecular skeletons involving 1,2,3-triazole units. Using allyl bromide in the reaction sequence results

Highly distinguishable isomeric states of a tripodal arylazopyrazole derivative on graphite through electron/hole-induced switching at ambient conditions

• Himani Malik,
• Sudha Devi,
• Debapriya Gupta,
• Ankit Kumar Gaur,
• Sugumar Venkataramani and
• Thiruvancheril G. Gopakumar

Beilstein J. Org. Chem. 2025, 21, 1496–1507, doi:10.3762/bjoc.21.112

• be attributed to the electronically decoupled individual photoswitchable units by 1,3,5-functionalization and attainment of non-planar geometry [30]. Molecular switches with multiple switching units having extended lifetime for their non-equilibrium states will be a unique tool for fabricating multi

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

• of amidyl radicals as HAT reagents, with a particular emphasis on their role in the intermolecular HAT process. We highlight key developments, mechanistic insights, and emerging strategies that harness the unique reactivity of amidyl radicals in the selective functionalization of a variety of

• substrates. Keywords: amidyl radicals; C–H; HAT reagents; hydrogen-atom-transfer; late-stage functionalization; Introduction C–H bonds are the predominant chemical bonds in organic compounds, and their direct conversion can rapidly and efficiently increase the complexity and functionality of organic

• molecules. On the other hand, C–H bonds exhibit low reactivity due to their relatively high bond dissociation energy (BDE) (Figure 1a). Therefore, the direct functionalization of C–H bonds is extremely challenging [1][2][3][4][5]. In recent decades, transition-metal-catalyzed C–H bond functionalization

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

• regioselective functionalization at the periphery of the PAHs. Besides triflyloxylation (42, 43), the introduction of one or two dichlorovinylene groups (43, 44) was observed. As in previous cases, the exact ratio of the products depended on the amount of DDQ and concentration of the precursor. Analysis of NICS

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

• , People’s Republic of China Zhejiang Lvgu Biopharmaceutical Co., Ltd., No.16 Bailian Road, Nanmingshan Street, Lishui City 323000, Zhejiang Province, China 10.3762/bjoc.21.98 Abstract The field of radical-mediated functionalization of N-arylacrylamides has experienced considerable advancements in recent

• , pharmaceutical development, and agrochemical production, representing one of the most significant classes of unsaturated organic compounds. Due to their broad availability and high reactivity, numerous elegant methodologies have been developed for their functionalization [1]. Among these, oxidative radical

• primarily focused on substrates containing activated alkenes tethered within the molecular framework. N-Arylacrylamides were employed as model substrates, and a diverse range of functionalization reagents, including those with benzylic C–H bonds, C(sp3)–H bonds adjacent to heteroatoms, di

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

• ][35][36][37][38][39]. The primary benefit of these reactions is introducing phosphorus fragments under mild reaction conditions into a diverse array of compounds that are inaccessible for functionalization employing other traditional approaches. After the pioneering work of Ji and Wei on aerobic

• precursors of α-substituted carbonyl compounds that have been recently applied as coupling partners for radical functionalization with the formation of C–C [63][64][65][66] and C–Het [67][68][69][70] bonds. The ready availability of enol acetates from the corresponding carbonyl compounds in just one

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

• blocks, we herein report electrophilic formylation of naphthalene-fused [3.3.3]- and [4.3.3]propellanes as the first selective single-point functionalization by virtue of through-space electronic communications between the naphthalene units. The propellane skeletons have well-defined 3D structures and

• ]. 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

• electrophilic functionalization. a) Synthesis of methylene-alternating copolymers of fully π-fused propellanes. DCE, 1,2-dichloroethane. b) 1H NMR (500 MHz, top) and 13C (126 MHz, bottom) NMR spectra of [4.3.3]_CH2OH and [4.3.3]_linear in CDCl3 at room temperature. Gas adsorption (filled circles) and desorption

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

• Julius Seumer Nicolai Ree Jan H. Jensen Department of Chemistry, University of Copenhagen, Copenhagen, Denmark 10.3762/bjoc.21.94 Abstract The mild and selective functionalization of carbon–hydrogen (C–H) bonds remains a pivotal challenge in organic synthesis, crucial for developing complex

• reliable regioselectivity predictions that are essential for accelerating innovation in materials science and medicinal chemistry. Keywords: C–H activation; chemical synthesis planning; directing groups; quantum mechanics; regioselectivity prediction; Introduction The activation and functionalization of

• bonds in organic chemicals. Therefore, their selective functionalization is essential for advancing the synthesis of complex molecules like pharmaceuticals, polymers, or agrochemicals [1][2][3]. Advancements in organometallic catalysis have facilitated significant progress in this area through C–H

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

• efficient design and synthesis of borrelidin fragments, aiding the advancement of borrelidin-based drug development. Future research in this area should continue to explore novel synthetic strategies to optimize the synthesis and functionalization of borrelidin fragments, further supporting their potential

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

• these derivatives, this study aims to offer direct synthetic guidance and important insights into the rational design of novel cinnamate molecules with promising potential as future drug candidates. The reaction mechanisms will be discussed briefly. 2 Carboxyl group functionalization 2.1 O/N-acylations

• ]. 3 Double-bond functionalization 3.1 Double-bond constructions 3.1.1 Conjugated alkyne hydrogenation: Mei and co-workers (2019) developed a Pd-catalyzed partial hydrogenation of conjugated alkynes in the presence of water as the hydrogen source and Mn as the reductant to give the corresponding

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

• , there is a lack of understanding of why the absorption and photoluminescence of D3 symmetrical triphenylmethyl radicals are so weak in the visible spectrum. While it is understood that the functionalization with donor moieties breaks the D3 symmetry, the ϕ varies greatly among different donors and also

• by the heavy atom effect of iodine, that also allows intersystem crossing (ISC) between triplet states in the matrix and the emissive doublet states of 3I-PTM. Interestingly, functionalization of all three para-positions in TTM with chalcogens in the form of aryloxy- and aryl thioethers leads to

• functionalization with a much broader variety of donors (and even acceptors) than is possible through a radical-mediated nucleophilic aromatic substitution (SRN1, see also below) [3][46][47]. The I-TTM has a maximum emission at λem = 578 nm and a ϕ of 3% (in cyclohexane), indicating that the symmetry does not seem

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

• expect this metal-free protocol for alkene amino-oxygenation to find widespread use in both academic and industrial synthetic chemistry. Poor performers. Existing reports of intramolecular alkene functionalization reactions with nitreniums have focused on amino-trifluoroacetoxylations. We show the first

Study of tribenzo[b,d,f]azepine as donor in D–A photocatalysts

• Katy Medrano-Uribe,
• Jorge Humbrías-Martín and
• Luca Dell’Amico

Beilstein J. Org. Chem. 2025, 21, 935–944, doi:10.3762/bjoc.21.76

• powerful tool for the construction and functionalization of organic molecules and materials. Thus, the scientific community has focused on the design and study of new organic molecules that can be used as photocatalysts, replacing generally more expensive metal-based complexes [1][2][3]. Furthermore, there