Recent advances in total synthesis of illisimonin A

• Juan Huang and
• Ming Yang

Beilstein J. Org. Chem. 2025, 21, 2571–2583, doi:10.3762/bjoc.21.199

• enantioenriched compound 33, a nickel-catalyzed hydrocyanation of the terminal alkyne was performed. Subsequent protection of the tertiary alcohol with TESOTf and reduction of the resulting cyanide to an aldehyde afforded compound 34 (Scheme 4). Addition of isopropenyllithium to aldehyde 34, followed by TES

Total syntheses of highly oxidative Ryania diterpenoids facilitated by innovations in synthetic strategies

• Zhi-Qi Cao,
• Jin-Bao Qiao and
• Yu-Ming Zhao

Beilstein J. Org. Chem. 2025, 21, 2553–2570, doi:10.3762/bjoc.21.198

• . This work not only demonstrates the efficacy of the titanium-mediated intramolecular alkyne-1,3-diketone coupling but also provides a novel strategic approach for synthesizing natural products within this structural class. The synthesis commenced from commercially available compound 83. Sequential

• alkyne difunctionalization, furyl group installation, Achmatowicz rearrangement, and subsequent functional group manipulations provided intermediates 84 and 85. C5-acylation and methylation under kinetically controlled conditions followed by Sonogashira coupling yielded cyclization precursor 89

• . Treatment of 89 with Ti(OiPr)4/iPrMgCl promoted the intramolecular stereoselective alkyne–1,3-dicarbonyl coupling, resulting in the construction of the AB ring system. This transformation afforded tricyclic compound 91 as the major product, accompanied by minor amounts of by-product 90. Subjecting 91 to

Rapid access to the core of malayamycin A by intramolecular dipolar cycloaddition

• Yilin Liu,
• Yuchen Yang,
• Chen Yang,
• Sha-Hua Huang,
• Jian Jin and
• Ran Hong

Beilstein J. Org. Chem. 2025, 21, 2542–2547, doi:10.3762/bjoc.21.196

• cleavage of the N–O bond, oxidation and Baeyer–Villiger oxidation. The starting functional groups (including alkyne and nitrone) for the proposed oxazoline were established in literature precedents [29][30][31]. Moreover, the readily available intermediate 8 [32] bearing three defined stereogenic centers

Pentacyclic aromatic heterocycles from Pd-catalyzed annulation of 1,5-diaryl-1,2,3-triazoles

• Kaylen D. Lathrum,
• Emily M. Hanneken,
• Katelyn R. Grzelak and
• James T. Fletcher

Beilstein J. Org. Chem. 2025, 21, 2524–2534, doi:10.3762/bjoc.21.194

• tandem deprotection/click chemistry followed by Pd-catalyzed annulation is summarized in Table 1. The alkyne-substituted analogs 1–6 [48][49][50][51][52] used in this study were prepared from commercially available aryl halides using microwave-promoted Sonogashira coupling (Table S1, Supporting

• Information File 1). Reaction of each TMS-protected alkyne with ortho-bromoazidobenzene produced 1,5-diaryl-1,2,3-triazole products 7–12, each possessing an ortho-bromoaryl reactive site necessary for the annulation step. Regioselective formation of 1,5-diaryl-1,2,3-triazoles 7–12 was achieved using a

• where the attachment of alkyne and azide functional groups was reversed, as summarized in Table 2. The azide analogs 19–24 [25][28][31][43] used in this study were prepared from commercially available amines using the Sandmeyer reaction (Table S2, Supporting Information File 1). Reaction of each azide

Catalytic enantioselective synthesis of selenium-containing atropisomers via C–Se bond formations

• Qi-Sen Gao,
• Zheng-Wei Wei and
• Zhi-Min Chen

Beilstein J. Org. Chem. 2025, 21, 2447–2455, doi:10.3762/bjoc.21.186

• alkyne insertion step may be rate-limiting, as it involves the participation of selenol, alkyne, and the rhodium catalyst. The Rh(III) mechanism appears to be more plausible than route B, which can be attributed to the enhanced ion-pairing effect resulting from the higher oxidation state of rhodium

Transformation of the cyclohexane ring to the cyclopentane fragment of biologically active compounds

• Natalya Akhmetdinova,
• Ilgiz Biktagirov and
• Liliya Kh. Faizullina

Beilstein J. Org. Chem. 2025, 21, 2416–2446, doi:10.3762/bjoc.21.185

• rearrangement of alkyne 230 into aldehyde 232, which contains two vicinal quaternary chiral centers at C8 and C10 (Scheme 41). (−)-Spirochensilide A belongs to an emerging and biologically important class of natural products with a unique spirocyclic core [99][100][101][102]. It is also a promising compound for

Comparative analysis of complanadine A total syntheses

• Reem Al-Ahmad and
• Mingji Dai

Beilstein J. Org. Chem. 2025, 21, 2334–2344, doi:10.3762/bjoc.21.178

• total synthesis – 2010 In 2010, Siegel and co-workers reported their total synthesis of complanadine A (Scheme 2). Their synthesis centres on two transition metal-catalyzed alkyne–alkyne–nitrile [2 + 2 + 2] cycloadditions to forge the two pyridine rings encoded by complanadine A [21]. Notably, the C2–C3

• intramolecular cyclization to afford alkyne–nitrile 19 for the first [2 + 2 + 2] cycloaddition with bis(trimethylsilyl)butadiyne (20). This transformation proceeded smoothly under thermal conditions with CpCo(CO)2 to afford 21 as the major regioisomer (rr = 25:1) [22]. Removal of the two TMS groups and

• reinstallation of a single TMS on the alkyne provided pyridyl-alkyne 22 for the second [2 + 2 + 2] cycloaddition reaction which proved nontrivial, with the protecting group on the secondary amine of the alkyne-nitrile moiety and the choice of ligand playing crucial roles. Specifically, when using 19 as the

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

• 1,5-enynes 1 as substrates involving alkyne alkoxylation and dienol ether aromaticity-driven processes (Scheme 2) [8]. The reaction pathway was decisively influenced by the choice of solvent. Under gold catalysis, with toluene as the solvent and 2 equiv of methanol serving as the nucleophile, the

• reaction proceeded via 5-endo-dig cyclization. This pathway involved enol ether attack on the gold-activated alkyne, leading to the formation of oxonium intermediate 2. Subsequently, nucleophilic addition of methanol culminated in the formation of indene motif 5 (Scheme 2, path a). When methanol served

• dual roles as solvent and nucleophile, the gold-catalyzed intermolecular Markovnikov addition of methanol to the gold-activated alkyne proceeded to afford dienol intermediate 4. The intermediate 4 subsequently underwent a regioselective 6-endo-trig cyclization, generating the naphthalene core 7 (Scheme

Synthesis of triazolo- and tetrazolo-fused 1,4-benzodiazepines via one-pot Ugi–azide and Cu-free click reactions

• Xiaoming Ma,
• Zijie Gao,
• Jiawei Niu,
• Wentao Shao,
• Shenghu Yan,
• Sai Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2025, 21, 2202–2210, doi:10.3762/bjoc.21.167

• /bjoc.21.167 Abstract A one-pot Ugi–azide reaction followed by intramolecular Cu-free azide–alkyne cycloaddition generates a polycyclic scaffold 7 bearing polycyclic triazole, tetrazole, and benzodiazepine rings. This method could be extended for obtaining a more complicated scaffold 8 containing a

• ]. We herein propose a one-pot synthesis involving an Ugi–azide 4-component (4-CR) reaction followed by lactamization and azide–alkyne cycloaddition for assembling triazole-fused and tetrazole-tethered 1,4-benzodiazepines 7 and triazole-, tetrazole-, and piperazinone-fused 1,4-benzodiazepines 8 (Scheme

• advantages over traditional copper-catalyzed azide–alkyne cycloaddition (CuAAC) reactions, including operational simplicity and the absence of metal contaminants, which is crucial for pharmaceutical applications. After having identified suitable reaction conditions of the Ugi–azide and click reactions for

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

• reaction mechanisms are disclosed if available. Keywords: alkyne; catalysis; cyclization; electrochemistry; five-membered ring; Introduction Organic five-membered rings, an essential class of organic compounds, not only are frequently used as important starting materials, intermediates or ligands in

• [61], [3 + 2] reductive cycloadditions of enal-alkyne [62], [2 + 2 + 1] cycloaddition of acetylenes [63] and cyclization of 1,6-enyne [64] were efficient approaches towards five-membered rings. Since Faraday synthesized hydrocarbons by employing electric current to an acetate solution [65], the use of

• electro-oxidative annulation of alkyne and benzamide afforded chiral pyridine-N-oxide [102], isoquinoline was synthesized successfully via electrochemical annulation of alkyne and benzamide [103] or imidate [104], electrochemical annulation of alkyne and acrylamide afforded α-pyrone and α-pyridone [105

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

• enantioselective reduction of 1,3-cyclohexanedione derivative 89 as the key transformation [72]. Both (−)-conidiogenones B–F (17–21) and (−)-12β-hydroxyconidiogenone C (22) were synthesized in a divergent manner. Their synthetic route began with the known terminal alkyne cyclohexanedione 89 [73]. As illustrated in

α-Ketoglutaric acid in Ugi reactions and Ugi/aza-Wittig tandem reactions

• Vladyslav O. Honcharov,
• Yana I. Sakhno,
• Olena H. Shvets,
• Vyacheslav E. Saraev,
• Svitlana V. Shishkina,
• Tetyana V. Shcherbakova and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2025, 21, 2021–2029, doi:10.3762/bjoc.21.157

• for the preparation of benzodiazepinone derivatives, which showed promising psychotropic effects [20][21][22][23][24], using a tandem combination of Ugi/azide–alkyne cycloaddition reactions. From this point of view, azido amines are promising reagents for use in the Ugi reaction, opening up the

Aryl iodane-induced cascade arylation–1,2-silyl shift–heterocyclization of propargylsilanes under copper catalysis

• Rasma Kroņkalne,
• Rūdolfs Beļaunieks,
• Armands Sebris,
• Anatoly Mishnev and
• Māris Turks

Beilstein J. Org. Chem. 2025, 21, 1984–1994, doi:10.3762/bjoc.21.154

• the reagents of choice for arylation reactions, where an umpolung of reactivity is required [1]. Arylations employing diaryl-λ3-iodanes can be performed under metal-free [2] or metal-catalyzed conditions. For alkyne arylations [Cu] [3] or [Pd] catalysis [4][5][6] is typically employed. Internal

• alkynes undergo 1,2-carbofunctionalization, where the highly electrophilic Ar–M species adds to the alkyne, generating a vinyl cation intermediate [7], which typically reacts with an internal nucleophile to form five- [8][9] or six-membered rings [7][9][10] (Scheme 1A). Thus far the internal nucleophilic

• reaction [17] and a [4 + 2] annulation reaction between o-carboxylic ester-containing diaryl-λ3-iodanes and some terminal alkynes [18]. Looking to expand the possibilities for terminal alkyne carbofunctionalization, we turned our attention to propargylsilanes, which are prone to undergo cationic

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

• norlignans hyperione A and ent-hyperione B was reported by the Deska group (Scheme 4) [33]. The synthesis commenced with a two-step conversion of ketone 22 to alkyne 23. Pd-catalyzed Tsuji-type reaction with zinc reagent 24, followed by acetonide hydrolysis, furnished allenic diol 25. Treating allenic diol

• enantioenriched monoester 53 in hand, the synthesis proceeded toward fredericamycin A (60) (Scheme 9). Dione 55, which was prepared from 53 in six steps, underwent addition with alkyne 56 followed by acylation of the resulting hydroxy group with compound 57 to yield ketone 58. A subsequent seven-step

• , ligand 205a proved to be suitable for 2-ethylpropane-1,3-diol (204). A three-step sequence then furnished enone 207, which underwent diastereoselective aldol reaction with fragment 208 to give compound 209. Alkyne 210, prepared from 209 in six steps, underwent addition with fragment 211 to yield compound

Rhodium-catalysed connective synthesis of diverse reactive probes bearing S(VI) electrophilic warheads

• Scott Rice,
• Julian Chesti,
• William R. T. Mosedale,
• Megan H. Wright,
• Stephen P. Marsden,
• Terry K. Smith and
• Adam Nelson

Beilstein J. Org. Chem. 2025, 21, 1924–1931, doi:10.3762/bjoc.21.150

• basis of these results, additional reactions involving the α-diazoamide substrates D4 (with a fluorosulfate warhead) and D5 (with a sulfonyltriazole warhead) were also executed. In addition to using these two α-diazoamide substrates with different warheads, two additional co-substrates bearing an alkyne

Photoswitches beyond azobenzene: a beginner’s guide

• Michela Marcon,
• Christoph Haag and
• Burkhard König

Beilstein J. Org. Chem. 2025, 21, 1808–1853, doi:10.3762/bjoc.21.143

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

• chiral ligand, which was modified on the upper rim of calixarene through hydrogen bonding. An azobenzene group was introduced as the photo-regulating part at the upper edge of calixarene. The alkyne at the lower edge of FC4AD was used to form self-assembled monolayers (SAMs) on a silicon surface through

Formal synthesis of a selective estrogen receptor modulator with tetrahydrofluorenone structure using [3 + 2 + 1] cycloaddition of yne-vinylcyclopropanes and CO

• Jing Zhang,
• Guanyu Zhang,
• Hongxi Bai and
• Zhi-Xiang Yu

Beilstein J. Org. Chem. 2025, 21, 1639–1644, doi:10.3762/bjoc.21.127

• alkyne moiety is installed via Sonogashira coupling reaction using aryl iodide 5. The cyclopropyl ring in 5 can be introduced via an SN2 reaction of compound 2 with tert-butyl cyclopropanecarboxylate (3). Scheme 5 summarizes the final successful execution of this route. The starting material 2 is a known

• % yield with a cyclopropyl group. Then reducing the carboxylate group in 4 with DIBAL-H afforded alcohol 5 in 67% yield. Next, Sonogashira coupling reaction between 5 and trimethylsilylacetylene generated 6 with an alkyne moiety quantitatively. After that, the hydroxy group in 6 was oxidized into a

Transition-state aromaticity and its relationship with reactivity in pericyclic reactions

• Israel Fernández

Beilstein J. Org. Chem. 2025, 21, 1613–1626, doi:10.3762/bjoc.21.125

• to the preparation of triazaphospholes and triazaarsoles, π-conjugated species with potential applications in materials science due to their luminescent properties [98]. However, these heavier alkyne analogues are typically kinetically unstable, which limits their use as dipolarophiles. Despite that

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

• CyreneTM, as a biomass-originated polar aprotic solvent, could be utilized as an alternative reaction medium for one-pot copper(I)-catalyzed azide–alkyne cycloaddition (click or CuAAC) reactions, for the synthesis of various 1,2,3-triazoles under mild conditions. Nineteen products involving N-substituted-4

• methods, the copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction, the so-called click reaction [7], has received substantial attention for the selective synthesis of various 1,2,3-triazoles that are of utmost importance in the synthesis of biologically active compounds such as active

• -triazoles in a less toxic and recyclable medium could further control and reduce the environmental impacts of this synthetically very important transformation. Herein, we report a study on the copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction in CyreneTM under mild conditions. Results and

Copper catalysis: a constantly evolving field

• Elena Fernández and
• Jaesook Yun

Beilstein J. Org. Chem. 2025, 21, 1477–1479, doi:10.3762/bjoc.21.109

• , Burley, Watson, and co-workers present a new synthesis of germyl triazoles from germyl alkynes through a copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction [6]. The resulting Ge-substituted triazoles could be further diversified. For example, through chemoselective transition-metal-catalyzed

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

• by trans-hydrostannation [50] of the corresponding alkyne precursors, so this report potentially introduced a new method for oxetane synthesis through an intramolecular Chan–Lam-type coupling. Due to the high reactivity of the exocyclic enol ether induced by the ring strain, 2-alkylidene

• ]. These oxetanone precursors are generated from easily accessible alkynylphosphonates 124 via gold-mediated alkyne oxidation by pyridine N-oxide 125 followed by a formal O–H-insertion of the resulting metallacarbene intermediate 128. The optimised procedure requires 5 mol % loadings of the gold catalyst

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

• and co-workers [55]. A palladium-catalysed variation of [3 + 2] annulation, accompanied by ring expansion [56], was used for the intermolecular reaction between acenes bearing alkyne substituents 55a–d and di-n-butylacetylene (56). The reaction gave a series of azulene-embedded isomers of linear

• intramolecular annulation of alkyne 123, followed by a Scholl-type oxidation of 124. Finally, double intramolecular C–H arylation catalysed by Pd(PCy3)2Cl2 gave non-alternant PAH 126 in an 18% yield. Interestingly, according to the calculated NICS values, all heptagons of 126 lost their aromatic character. Later

• –base reaction. Cyclization of alkynes: The extension of π-conjugation in polycyclic aromatic hydrocarbons (PAHs) through alkyne-benzannulation reactions has become an increasingly popular method in recent years [91]. Such benzannulations can be mediated by Brønsted acids, Lewis acids or transition

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

• different substituents, including aryl, heteroaryl, and alkyl groups at the terminal alkyne, were well tolerated, yielding moderate to good results (16aa–da). Furthermore, variations in the nitrile reaction partners, such as butyronitrile (16ea), 2-phenylacetonitrile (16fa), malononitrile (16ga), and 3-oxo

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

• construction, alkyne hydrogenation, ylide and carbene reaction, metathesis, E/Z isomerization, and other methods, including Cα and Cβ functionalizations. Preparing various functional group-tethered aromatic groups can be achieved by directly installing an aromatic group via cross-coupling reactions and other

• -branched (L/B) selectivity of >20:1. The reaction involves the formation of palladium hydride (Pd–H) 270 as the key species followed by alkyne and CO insertion reactions via 271 and 272 (Scheme 68A) [116]. On the one hand, Jia and co-workers (2021) utilized environmentally benign water as the hydrogen

• source to perform the Pd-catalyzed alkyne hydrocarbonylation with CO via 276 to obtain the corresponding cinnamic acids 273–275 in good yields (Scheme 68B) [117]. In addition, a gram scale operation has been carried out. Li and co-workers (2019) employed a non-precious transition metal, ligand-free Fe3