Assembly strategy for thieno[3,2-b]thiophenes via a disulfide intermediate derived from 3-nitrothiophene-2,5-dicarboxylate

• Roman A. Irgashev

Beilstein J. Org. Chem. 2025, 21, 2489–2497, doi:10.3762/bjoc.21.191

• ]. In route IV, cleavage of the ethyl xanthate group in the starting substrate by NaOMe generates a thiolate intermediate, which undergoes S-alkylation and subsequent NaOMe-promoted cyclization to afford the 3-hydroxy-TT [28]. In our recent works, it was presented an effective strategy for synthesizing

• reaction conditions to release thiolate species capable of reacting separately with ester 1 to form compound 2. Disulfide 3 was found to be an accessible and stable precursor of dimethyl 3-mercaptothiophene-2,5-dicarboxylate, a molecule that is suitable for S-alkylation. In this regard, reductive cleavage

• cleavage of the S–S bond and the subsequent S-alkylation reaction were successful. To suppress the side reaction and improve reduction efficiency, we next employed DMF as a polar aprotic solvent. In Table 2, entry 4, reduction of disulfide 3 in DMF at 75 °C with NaBH4 was complete within 15 min. The excess

Palladium-catalyzed regioselective C1-selective nitration of carbazoles

• Vikash Kumar,
• Jyothis Dharaniyedath,
• Aiswarya T P,
• Sk Ariyan,
• Chitrothu Venkatesh and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2025, 21, 2479–2488, doi:10.3762/bjoc.21.190

• after 2 hours, indicating that C–H bond cleavage is kinetically relevant and likely involved in the rate-determining step (Scheme 5b). To gain additional mechanistic insight, we synthesized palladacycle intermediate 6 following the reported procedure [58]. Then, the reaction was carried out using

• ][78][79][80], a plausible catalytic cycle is proposed (Figure 2). The catalytic cycle commences with the formation of active palladium(II) species 7 in the presence of AgNO3. Coordination of the pyridyl group of 1a to Pd(NO₃)₂ is followed by irreversible C–H bond cleavage via cyclopalladation to form

Synthesis of the tetracyclic skeleton of Aspidosperma alkaloids via PET-initiated cationic radical-derived interrupted [2 + 2]/retro-Mannich reaction

• Ru-Dong Liu,
• Jian-Yu Long,
• Zhi-Lin Song,
• Zhen Yang and
• Zhong-Chao Zhang

Beilstein J. Org. Chem. 2025, 21, 2470–2478, doi:10.3762/bjoc.21.189

• that the rate-determining step of the key PET reaction involved C19–C12 bond formation and C19–C3 bond cleavage. Investigation of the bond length changes along the IRC path, spin density, and NBO analysis indicated that this process is neither strictly concerted nor stepwise, but falls in between, and

• photoredox catalysis) processes [8][9][10]. Cyclobutenone (A) is a versatile C4 synthon [11] – its [2 + 2] photocyclization yields B, featuring a strained bicyclo[2.2.0]hexane unit [12], which can fragment to form C (Figure 1a) [13][14]. However, competitive C1–C4 bond cleavage under irradiation or heating

• current interest in the synthesis of complex natural products via photochemical reactions, we decided to achieve such an unusual bond cleavage (Figure 1a, path A) of cyclobutenone by generating a radical cation species via a PET reaction. The synthetic plan is shown in Figure 1c and includes a PET

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

• contraction of six-membered cycles in the synthesis of functionalized cyclopentane/enones, which are biologically active compounds. The main synthetic methods of ring contraction (ozonolysis–aldol condensation, ozonolysis–Dieckmann reaction, Baeyer–Villiger cleavage–Dieckmann reaction) and rearrangements

• cyclohexane/ene ring contraction. The structure of the review includes examples of simple transformations (ozonolysis–aldol condensation, ozonolysis–Dieckmann reaction, and Baeyer–Villiger cleavage–Dieckmann reaction) and rearrangements (photochemical, benzil, semi-pinacol, Wolff, Meinwald, Wagner–Meerwein

• and Favorskii reaction), using oxidants based on thallium and iodine, with a focus on recent works published in the period from 2014 to 2024. Review 1 Recyclization A common method for converting cyclohexene 1 into cyclopentene 2 is the ozonolytic cleavage of the double bond followed by intramolecular

An Fe(II)-catalyzed synthesis of spiro[indoline-3,2'-pyrrolidine] derivatives

• Elizaveta V. Gradova,
• Nikita A. Ozhegov,
• Roman O. Shcherbakov,
• Alexander G. Tkachenko,
• Larisa Y. Nesterova,
• Elena Y. Mendogralo and
• Maxim G. Uchuskin

Beilstein J. Org. Chem. 2025, 21, 2383–2388, doi:10.3762/bjoc.21.183

• bond cleavage to generate an N-imidoyl radical intermediate that undergoes intramolecular cyclization to yield the spirocyclic product (Scheme 1, path g) [14]. Notably, iron is known to exhibit similar behavior in single-electron transfer (SET) processes [15][16][17]. In fact, we previously

• pathway (Scheme 4). Initial Fe(II)-mediated reductive cleavage of the N–O bond in the ketoxime acetate generates an iminyl radical. This is followed by a 5-exo-trig cyclization to form a carbon-centered radical. Final single-electron oxidation by Fe(III) delivers the desired spirocyclic product. All

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

• TMSN3 recently developed by Xu and co-workers [34]. Mukaiyama conjugate addition between 60 and 61 promoted by Tf2NH followed by a one-pot enol ether hydrolysis gave 62 as a mixture of inconsequential stereoisomers. Subsequent oxidative cleavage of the terminal olefin of 62 using ozonolysis followed by

Recent advances in Norrish–Yang cyclization and dicarbonyl photoredox reactions for natural product synthesis

• Peng-Xi Luo,
• Jin-Xuan Yang,
• Shao-Min Fu and
• Bo Liu

Beilstein J. Org. Chem. 2025, 21, 2315–2333, doi:10.3762/bjoc.21.177

• Norrish–Yang cyclization, followed by a strain-release Pd-catalyzed C–C cleavage/cross-coupling protocol [9][11]; the strategy was subsequently applied to the total synthesis of lycoplatyrine A (89) in 2021 [38]. Isolated by Low’s group [39], lycoplatyrine A (89) belongs to the lycodine-type Lycopodium

• to construct a β-lactam, an α-metallated piperidine equivalent, overcoming poor yields and stereoselectivity in traditional methods. Its palladium-catalyzed cross-coupling with 2-bromolycodine via β-lactam C–C cleavage enabled stereoretentive coupling, efficiently synthesizing lycoplatyrine A and its

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

• has been largely supplanted by greener methods employing less-toxic reagents. Using alternative methods, radicals can be generated by hydrogen atom transfer (HAT), resulting in the homolytic cleavage of a carbon–hydrogen bond. Other approaches for radical generation in modern radical transformations

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

• 60 °C initiated nickel-mediated intramolecular [2 + 2] cycloaddition to form dihydrocyclobuta[c]quinolin-3-one framework 164. Conversely, when the temperature was elevated to 140 °C, thermal ring-expansion of the four-membered intermediate was induced through C–C bond cleavage/reorganization

• cleavage to form the boronated phenanthrene framework 170. It is worth mentioning that a unique skeleton rearrangement, supported by DFT calculations, was proposed in this work, which was unprecedented in BiCl3-promoted cyclization. Conclusion This comprehensive review has systematically delineated the

A chiral LC–MS strategy for stereochemical assignment of natural products sharing a 3-methylpent-4-en-2-ol moiety in their terminal structures

• Rei Suo,
• Raku Irie,
• Hinako Nakayama,
• Yuta Ishimaru,
• Yuya Akama,
• Masato Oikawa and
• Shiro Itoi

Beilstein J. Org. Chem. 2025, 21, 2243–2249, doi:10.3762/bjoc.21.171

• Discussion Our degradation strategy of natural products bearing an MPO moiety includes (1) acylation of hydroxy group, (2) oxidative cleavage of olefin to generate 3-acyloxy-2-methylbutanoic acid, and (3) its methyl esterification (Scheme 1A). We initially investigated derivatization strategies to enable LC

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

• occurred to give a radical cation PhSeSePh•+ at the anode. The subsequent cleavage of Se–Se bond formed a radical PhSe• and a cation PhSe+. Further additional oxidation of PhSe• yielded another PhSe+, which worked as the major reactive species and quickly added to C≡C in 13a to form intermediate A. Finally

C2 to C6 biobased carbonyl platforms for fine chemistry

• Jingjing Jiang,
• Muhammad Noman Haider Tariq,
• Florence Popowycz,
• Yanlong Gu and
• Yves Queneau

Beilstein J. Org. Chem. 2025, 21, 2103–2172, doi:10.3762/bjoc.21.165

• hydrogenation to produce furfuryl alcohol. This latter is a versatile intermediate for the production of resins, coatings, polymers and used as a solvent. It can also be converted into other chemicals through oxidative cleavage, over-reduction and etherification (Scheme 49) [177]. Zhang et al. reported the use

• of the system in favor of meta isomer. Acidic cleavage followed by reductive amination afforded m-xylylenediamine (Scheme 54). Tetrahydrofuran-derived amines were prepared from furfural via a one-pot two-step reaction. The condensation of furfural with ketones over Amberlyst-26 as catalyst produced

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

• group [35][36][37]. This catalytic system efficiently overcame the challenge and furnished the coupling product 46 in high yield. Oxidative cleavage of the double bond in 46 followed by Mg(II)-mediated chelation-controlled Friedel–Crafts cyclization delivered secondary alcohol 47, which was elaborated

• intramolecular Diels–Alder reaction generated tricyclo[3.2.1.02,7]-octene 113. A two-step transformation including HAT hydrogenation and acetal C–H oxidation with RuCl3/NaIO4, 113 was converted into ketoester 114. The TFA-mediated C13–C15 bond cleavage of 114 proceed smoothly to give ring-opening products, which

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

• as the activating agent under standard peptide coupling conditions. Cleavage of the Boc-protecting group with TFA afforded the target 6-oxoindolo[1,2-c]quinazoline-12-carboxamides 7a–c (Scheme 2). 3-Aminomethylindole derivatives represent a well-established class of compounds with diverse biological

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

• propose the biosynthetic pathway, which has not yet been reported in Duh’s isolation report (Scheme 1a). In our proposal, the linear sesquiterpenoid trans-nerolidol (1) with a chiral tertiary alcohol undergoes dihydroxylation to generate triol 2, which further proceeds a C–C bond cleavage to afford

• evidences of chemical transformations. Thus, a bioinspired total synthesis was investigated (Scheme 1b). Synthetically, we did not start from trans-nerolidol (1) to construct a C–C bond cleavage. Instead, a convergent coupling approach was selected to quickly access the aldehyde precursor. Phenyl sulfide 5

• unreacted, which released the secondary alcohol, followed by BCl3-promoted selective cleavage of the isopropyl and one methyl protection ultimately furnished thenatural product fusarentin 6-methyl ether. With fusarentin 6-methyl ether in hand, we explored the bioinspired oxidation/oxa-Michael addition. This

Understanding the origin of stereoselectivity in the photochemical denitrogenation of 2,3-diazabicyclo[2.2.1]heptene and its derivatives with non-adiabatic molecular dynamics

• Leticia A. Gomes and
• Steven A. Lopez

Beilstein J. Org. Chem. 2025, 21, 2007–2020, doi:10.3762/bjoc.21.156

• calculations have provided valuable insights into the photochemical stereoselectivities of cyclic azoalkenes. In 1998, Yamamoto and co-workers investigated the reaction paths for α-C–N and β-C–C bond cleavage during the direct and sensitized photolysis of DBH [81]. The minimum energy geometries in S0, S1, T1

• the denitrogenation mechanism of 7,7‐diethoxy‐2,3‐diazabicyclo[2.2.1]hept‐2‐ene, showing that a stepwise C–N-bond cleavage is energetically favored using broken‐symmetry (BS)‐(U)CCSD/6‐31G(d) and suggested that an equatorial conformation of the diazinyl diradical leads to the formation of the inverted

• favorable. All MECI structures show partial stereochemical inversion. Following the initial σCN-bond cleavage, the carbon atom still bonded to N₂ begins to move towards inversion, indicating that dynamic effects help promote the stereoselective inversion. Conclusion We used multiconfigurational quantum

Measuring the stereogenic remoteness in non-central chirality: a stereocontrol connectivity index for asymmetric reactions

• Ivan Keng Wee On,
• Yu Kun Choo,
• Sambhav Baid and
• Ye Zhu

Beilstein J. Org. Chem. 2025, 21, 1995–2006, doi:10.3762/bjoc.21.155

• chirality, the pairs of substituents (a and b, c and d) are separated in space because the stereogenic scaffolds span multiple atoms. Consequently, bond cleavage and formation occur at positions that are distant from the stereogenic elements and remote from the actual points of differentiation among the

• index (Scheme 2). A detailed process for assigning the index is shown in Scheme 2A for asymmetric hydrogenation of 2-butanone [1]. The atoms involved in bond cleavage and bond formation are highlighted in orange color. The atoms responsible for assignment of the stereochemical configuration of the

• rules, and the set(s) that do not involve bond formation and bond cleavage are used to identify the points of stereochemical differentiation. Different stereocontrol strategies could be employed to achieve asymmetric synthesis of axially chiral biaryls (Scheme 3). The stereocontrol connectivity indices

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

• hydroxy group and auxiliary cleavage, thioester 92 was obtained. Five additional steps converted 92 into lactone 93. Oxidative cleavage of the diol group in 93 and following coupling with fragment 94 gave compound 95, which was further elaborated to leustroducsin B (96) in 15 steps. In 2013, Nanda and co

• . Epoxidation of 131 followed by methylation generated epoxide 132. Construction of the lactone moiety commenced with the oxidative cleavage of the double bond, and the resulting carboxylic acid underwent intramolecular cyclization in the presence of BF3·Et2O to give lactone 133. Subsequent hydride reduction

• monobenzoate 142 in 94% yield along with 4% yield of its diastereomer (dr = 24:1). Following a four-step conversion of 142 to epoxide 143, reductive cleavage produced a diol intermediate, which was subjected to chemoselective glycosylation with compound 144 to provide compound 145. After a four-step

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

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

• -disubstituted and 4-substituted quinoline molecules. The developed strategy involves an earth-abundant Fe-catalyzed C(sp2)–C(sp2) bond cleavage of styrene, followed by the hydroamination of the cleaved synthons with arylamines and subsequent C–H annulation to yield two valuable quinoline derivatives. Key

• promising industrial relevance. Oxidative cleavage of alkenes to yield carbonyl compounds is one of the key transformations in synthetic organic chemistry [41][42]. Over the past two decades, this field has witnessed significant advancements, primarily through the use of organic oxidants and transition

• -metal catalysts. One of the key transformations in organic synthesis is the selective oxidative cleavage of alkenes to yield ketones or aldehydes [43][44][45][46][47]. Traditionally, such transformations have been achieved using various oxidizing agents, transition-metal-based systems, organo- and

Preparation of a furfural-derived enantioenriched vinyloxazoline building block and exploring its reactivity

• Madara Darzina,
• Anna Lielpetere and
• Aigars Jirgensons

Beilstein J. Org. Chem. 2025, 21, 1737–1741, doi:10.3762/bjoc.21.136

• methoxymethyl group cleavage, O-to-N rearrangement, and isomerization of the double bond. An oxazoline ring formation in the resulting unsaturated amides provided the corresponding enantioenriched vinyloxazoline. The reactivity of the electron-deficient double bond in the vinyloxazoline was explored in several

• . Cleavage of the N-Alloc group leading to a mixture of isomers cis-S-5 and trans-S-5. Cleavage of the N-Alloc group with PdCl2(S-BINAP) leading to trans-S-5 and trans-R-5. Cyclization of amides trans-S-5 and trans-R-5 to oxazolines S-6 and R-6. aza-Diels–Alder reaction of vinyloxazoline S-6 with TsNCO. The

3-Aryl-2H-azirines as annulation reagents in the Ni(II)-catalyzed synthesis of 1H-benzo[4,5]thieno[3,2-b]pyrroles

• Julia I. Pavlenko,
• Pavel A. Sakharov,
• Anastasiya V. Agafonova,
• Derenik A. Isadzhanyan,
• Alexander F. Khlebnikov and
• Mikhail S. Novikov

Beilstein J. Org. Chem. 2025, 21, 1595–1602, doi:10.3762/bjoc.21.123

• to the azirine C=N bond, followed by cyclization and the aziridine ring opening into the [3 + 2] cycloaddition product 5 (Scheme 3). It is noteworthy that the annulation proceeds via the azirine N‒C3 bond cleavage. Elimination of the methoxycarbonyl group most likely occurs under the action of

• the NHC-complex, IPrCuCl, the formation of cycloadduct 11 was detected, which was isolated in 10% yield (Scheme 6). The formation of this compound implies the cleavage of the azirine N−C2 bond, indicating that the IPrCuCl-catalyzed reaction proceeds by a different mechanism, likely involving the

Wittig reaction of cyclobisbiphenylenecarbonyl

• Taito Moribe,
• Junichiro Hirano,
• Hideaki Takano,
• Hiroshi Shinokubo and
• Norihito Fukui

Beilstein J. Org. Chem. 2025, 21, 1454–1461, doi:10.3762/bjoc.21.107

• dibenzo[g,p]chrysene (DBC, 2) via oxidative inner-bond cleavage (Figure 1) [16][17]. CBBC 1 was first synthesized by Suszko and Schillak in 1934 using sodium dichromate as an oxidant [16]. Recently, our group developed a scalable, catalytic, and enantioselective protocol to furnish CBBC 1 [17]. Several

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

• from simple cyclopentenones 71 and symmetric alkenes 72 (Scheme 20) [60]. Although the reaction is rather low-yielding (mostly below 30%), it tends to give high diastereoselectivities. The mechanism is believed to proceed through the following steps: [2 + 2] photocycloaddition, Norrish-type I cleavage

• halogens, nitriles, alkenes and heteroaryls. On the other hand, this methodology suffers from relatively low diastereoselectivity as the dr lies between 1:1 and 2:1. DFT calculations suggested the reaction proceeds through nitrogen elimination, oxonium ylide 119 formation, homolytic cleavage and radical

• 2020, Bull et al. published a short synthesis of 3-aryloxetan-3-carboxylic acids 152 employing a Friedel–Crafts alkylation (which builds on their previous alkylation of phenols [87]) and a selective furan oxidative cleavage (Scheme 37) [88]. The oxidation protocol uses a catalytic amount of a high

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

• amidyl radicals from HRP: (a) direct single-electron oxidation of amide HRP in the presence of photocatalyst and a base via a proton-coupled electron transfer (PCET) process by the cleavage of the N–H bond; (b) single-electron reduction of HRP catalyzed by photocatalyst via a single-electron transfer

• (SET) process by the cleavage of the N–O bond; (c) direct homolytic cleavage of weak N–S or N–X bonds in HRP initiated in the presence of visible light; (d) the intersystem crossing (ISC) of S1 to T1 state directly from the amide anion. This review is organized by bond cleavage type, offering a deep

• with a systematic understanding and strategic toolkit, thereby propelling the development of direct functionalization of C–H, B–H, Si–H, and Ge–H techniques in modern organic synthesis. Most of the photocatalysts used in this review are listed in Figure 3. Review Amidyl radical from N–H bond cleavage N