Advances in Zr-mediated radical transformations and applications to total synthesis

• Hiroshige Ogawa and
• Hugh Nakamura

Beilstein J. Org. Chem. 2026, 22, 71–87, doi:10.3762/bjoc.22.3

• corresponding vic-bis(dithiane) derivatives 16a–d. In 2018, Milsmann et al. reported the dimerization of benzyl bromide using a zirconium complex as a photosensitizer (Scheme 4) [14]. Heating a zirconium precursor with the pincer-type ligand 17, which can be synthesized in three steps from commercially

• a photosensitizer, together with compound 22 as a sacrificial reductant, in the dimerization of benzyl bromide (19). The desired dimerized product 20 was obtained in 40% yield. This study highlights the potential of zirconium complexes as a photoredox catalyst, pointing to promising opportunities

• development of efficient synthetic methods for its construction remains in high demand. Benzyl chlorides, which are inexpensive and readily available, have attracted attention as promising feedstocks. Against this background, Ota and Yamaguchi et al. in 2025 reported the dimerization of benzyl chlorides using

Reactivity umpolung of the cycloheptatriene core in hexa(methoxycarbonyl)cycloheptatriene

• Dmitry N. Platonov,
• Alexander Yu. Belyy,
• Rinat F. Salikov,
• Kirill S. Erokhin and
• Yury V. Tomilov

Beilstein J. Org. Chem. 2026, 22, 64–70, doi:10.3762/bjoc.22.2

• halogenation reactions. The reactions with methyl iodide and propargyl bromide resulted in equilibrium mixtures of α-alkylated cycloheptatrienes 5d,e and the corresponding norcaradienes 6d,e. At the same time, benzyl bromide afforded pure norcaradiene 6f in a good yield. Apparently, the formation of a pure

Synthesis and applications of alkenyl chlorides (vinyl chlorides): a review

• Daniel S. Müller

Beilstein J. Org. Chem. 2026, 22, 1–63, doi:10.3762/bjoc.22.1

• mixtures of E- and Z-isomers (Scheme 40C). Notably, in these less-selective cases, excess alkyne was required to achieve synthetically useful yields. For example, compound 221 was obtained in only 15% yield when phenylacetylene and benzyl chloride were employed in a 1:1 molar ratio. Mayr and co-workers

• hydrocarbon precursors using DDQ, followed by interception with alkynes, was reported by Shi and co-workers (Scheme 47) [154]. However, the authors did not clarify whether the corresponding benzyl chloride was formed in the absence of the alkyne trapping agent (trapping of cationic intermediate by chloride

• Rodriguez subsequently reported a slightly modified procedure in 2017 (Scheme 67) [209]. In 2008, Charette reported that treatment of benzyl bromides with “NaICHCl” furnished the corresponding styrenyl chlorides in good yields and with high E-selectivity (Scheme 68) [210]. Pace and co-workers recently

Sustainable electrochemical synthesis of aliphatic nitro-NNO-azoxy compounds employing ammonium dinitramide and their in vitro evaluation as potential nitric oxide donors and fungicides

• Alexander S. Budnikov,
• Nikita E. Leonov,
• Michael S. Klenov,
• Andrey A. Kulikov,
• Igor B. Krylov,
• Timofey A. Kudryashev,
• Aleksandr M. Churakov,
• Alexander O. Terent’ev and
• Vladimir A. Tartakovsky

Beilstein J. Org. Chem. 2025, 21, 2739–2754, doi:10.3762/bjoc.21.211

• structure of 2c was confirmed by single-crystal X-ray analysis. The benzyl moiety was also tolerated, and the corresponding product 2e was obtained in 57% yield. 2,2-Dimethyl-5-nitro-5-nitroso-1,3-dioxane (1f) was successfully employed under the reaction conditions, leading to the formation of product 2f in

Recent advancements in the synthesis of Veratrum alkaloids

• Morwenna Mögel,
• David Berger and
• Philipp Heretsch

Beilstein J. Org. Chem. 2025, 21, 2657–2693, doi:10.3762/bjoc.21.206

• attributed to the hindrance by the axial benzyl ether group on one side, and the C7 axial TBS ether group on the other. Removal of the silyl groups at C7 and C20 with CsF was followed by dihydroxylation of the C14,15-double bond, and the major product 105 was determined to be the desired α-diol by 1H–1H

• -NOESY and DFT calculations. The tertiary amine was masked as the hydrochloride salt with concomitant ketal deprotection, which was followed by hydrogenation to remove the benzyl protecting group to obtain (±)-4-methylenegermine hydrochloride (17·HCl) in 31 steps (LLS from commercial materials) and an

• -valerolactone). This was followed by an azide-Mitsunobu reaction and auxiliary removal with LiOBn to yield β-azido ester 115. Staudinger reduction of the azide moiety with PPh3 was accompanied by spontaneous cyclization to the lactam. The benzyl ester was converted to the aldehyde (2 steps), followed by

Visible-light-driven NHC and organophotoredox dual catalysis for the synthesis of carbonyl compounds

• Vasudevan Dhayalan

Beilstein J. Org. Chem. 2025, 21, 2584–2603, doi:10.3762/bjoc.21.200

• -photocatalyst, leading to various β-aryl keto ester derivatives 20 in good to excellent yields. The key steps of the reactions undergo radical–radical cross-coupling with the alkyl ester radical E and benzyl radical B to afford the desired keto-esters 20 in up to 88% yield. This catalytic process displayed good

• catalyst. The anticipated meta-acylation product 32 was achieved through highly selective C(sp3)–C(sp3)-radical–radical cross-coupling between the cyclohexadienyl radical C and the benzyl radical species F, formed via single-electron reduction. This photochemical method overturns the traditional ortho and

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

• trans-esterification to give lactone 78. The resulting tertiary alcohol was protected as its benzyl ether to afford 79. A two-step oxidation protocol, analogous to Yang’s method, introduced the C8 carbonyl group, yielding 80. The final ring was closed via an intramolecular aldol reaction following

• Yang’s conditions [30], assembling the trans-pentalene to give 81. Finally, deprotection of the benzyl ether delivered (−)-illisimonin A (1). Lu’s gram-scale synthesis of illisimonin A In 2025, the Lu group reported a gram-scale total synthesis of illisimonin A in 15 steps from commercially available

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

• . While its mechanism remains incompletely understood, this additive’s unique efficacy in such transformations is unprecedented. Subsequent steps involved hydroxylation of the double bond and the protection of the vicinal diol as a dimethyl ketal giving ester 100. Oxidative dehydrogenation, benzyl

Isoorotamide-based peptide nucleic acid nucleobases with extended linkers aimed at distal base recognition of adenosine in double helical RNA

• Grant D. Walby,
• Brandon R. Tessier,
• Tristan L. Mabee,
• Jennah M. Hoke,
• Hallie M. Bleam,
• Angelina Giglio-Tos,
• Emily E. Harding,
• Vladislavs Baskevics,
• Martins Katkevics,
• Eriks Rozners and
• James A. MacKay

Beilstein J. Org. Chem. 2025, 21, 2513–2523, doi:10.3762/bjoc.21.193

• addition of the acyl chloride to excess 9 was important to avoid forming bis-acylation of the phenylenediamine. The carboxylic acid 13 was formed using a microwave-promoted ring opening of glutaric anhydride (11) and benzyl-protected PNA backbone 12 [38]. A series of optimizations was performed in a

• perform equally well using conventional heating methods. Aniline 10 and carboxylic acid 13 were combined under standard (HBTU) amide coupling conditions to afford benzyl ester 14 in 52% yield. Compound 14 was subsequently debenzylated via hydrogenolysis to afford the target Db2 monomer 15 in 77% yield

• -nitroaniline into benzyl acrylate to afford compound 17 in 57% yield (Scheme 3). Aniline 17 then was subjected to a three-step Boc protection, nitro reduction, and coupling with isoorotic acid derivative 6 that afforded 18 in 39% yield over 3 steps. The benzyl ester was then cleaved under hydrogenolysis

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

• benzyl halides and other electrophiles were used under optimal reaction conditions to obtain various 3-(alkylthio)thiophene-2,5-dicarboxylates. Among them, compounds 4b–g, bearing benzylthio substituents, were prepared using different benzyl-type alkylating agents. It was found that the reaction

• (77% yield). For product 4b, methyl 4-(bromomethyl)benzoate was employed as the alkylating agent. In all other cases, benzyl chlorides were used for the alkylation. The alkylation with chloroacetonitrile afforded 3-(cyanomethyl)thio derivative 5a in 48% yield, shown in parenthesis in Scheme 6, while

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

• the formation of benzyl radical IN2, which has a boat-like seven-membered ring. This structural feature may facilitate formation of the C19–C12 bond, even in the presence of critical steric hindrance between the C5 quaternary carbon and the indole moiety. Further DFT investigation proved challenging

Ex-situ generation of gaseous nitriles in two-chamber glassware for facile haloacetimidate synthesis

• Nikolai B. Akselvoll,
• Jonas T. Larsen and
• Christian M. Pedersen

Beilstein J. Org. Chem. 2025, 21, 2465–2469, doi:10.3762/bjoc.21.188

• glycosyl trifluoroacetimidates are more stable and hence easier to purify and store, whereas the more activated benzyl-protected analog 3 is unstable and decomposes in contact with silica unless the silica had been deactivated with triethylamine in the eluent. It was furthermore found that the best yields

• synthesis of several glycosyl haloacetimidates and benzyl fluoroacetimidates, with different substituent patterns. The method allows for a larger substrate scope of halonitriles than earlier methods and is easily facilitated by low cost commercially available equipment. Examples of methods for the synthesis

The intramolecular stabilizing effects of O-benzoyl substituents as a driving force of the acid-promoted pyranoside-into-furanoside rearrangement

• Alexey G. Gerbst,
• Sofya P. Nikogosova,
• Darya A. Rastrepaeva,
• Dmitry A. Argunov,
• Vadim B. Krylov and
• Nikolay E. Nifantiev

Beilstein J. Org. Chem. 2025, 21, 2456–2464, doi:10.3762/bjoc.21.187

• the furanoside form. Thus it is possible to determine preliminary that the current PIF-rearrangement is regulated by thermodynamics in case of methyl-aglycons and by mechanistic restrictions in case of the phenyl-aglycon. Abbreviations Bz: benzoate; Bn: benzyl; TIPS: triisopropylsilyl; TBDPS: tert

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

• (BnOH, 2,4,6-collidine, 160 °C). The desired benzyl ester 126 was isolated as single diastereomer with a yield of 56% yield. Reduction of 126 with LiAlH4 followed by oxidation with Dess–Martin periodinane (DMP) led to the synthesis of a key aldehyde 127, with a yield of 75% in two steps. The target

• phase. Benzyl esters were cleaved, and the resulting carboxylic acids were converted into corresponding benzylammonium salts by addition of two equivalents of benzylamine. Subsequent irradiation of these salts in the form of a crystalline suspension in hexane led to ring-contraction products with a 95

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

• alkyne-nitrile partner, the undesired regioisomer (2,2’-bipyridyl product) was obtained as the major product. Switching the alkyne-nitrile partner from 19, bearing a benzyl group, to the formyl-substituted partner 23, combined with addition of 8 equivalents of PPh3, successfully inverted the

• regioselectivity and gave the desired cycloadduct 24 as the major product in 56% yield. From here on, removal of the TMS group with TBAF, followed by hydrogenolytic removal of the benzyl group and acidic hydrolysis of the formyl group, completed Siegel’s total synthesis of complanadine A. In addition, this

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

• involved at the ethyne moiety like substituted phenyl (30b–e), benzodioxole (30f), naphthyl (30g), thienyl (30h), pyridinyl (30i), furyl (30j), benzofuranyl (30k), alkyl (30l, 30m), cycloalkyl (30n–p) and trimethylsilyl (30r). This reaction was also compatible with benzyl ester (30s), propynyl ester (30t

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

• electrocatalyst supported on nitrogen-doped carbon nanosheets (Cu/NCNSs). This catalyst exhibits high activity for the oxidation of various substrates, including GLY, gluconic acid (GLU), 5-hydroxymethylfurfural (HMF), benzyl alcohol (BA), furfuryl alcohol (FA), and ethylene glycol (EG) (Scheme 7) [35]. Park et

Further elaboration of the stereodivergent approach to chaetominine-type alkaloids: synthesis of the reported structures of aspera chaetominines A and B and revised structure of aspera chaetominine B

• Jin-Fang Lü,
• Jiang-Feng Wu,
• Jian-Liang Ye and
• Pei-Qiang Huang

Beilstein J. Org. Chem. 2025, 21, 2072–2081, doi:10.3762/bjoc.21.162

• our third-generation strategy featuring the employment of benzyl ʟ-valinate as the coupling component [63], tripeptide derivative 28 was synthesized in three steps. Exposure of 28 to DMDO in acetone followed by treating the resulting intermediates with Na2SO3 produced the proposed structure of aspera

Photochemical reduction of acylimidazolium salts

• Michael Jakob,
• Nick Bechler,
• Hassan Abdelwahab,
• Fabian Weber,
• Janos Wasternack,
• Leonardo Kleebauer,
• Jan P. Götze and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2025, 21, 1973–1983, doi:10.3762/bjoc.21.153

• electron to compound 3 could explain the formation of the fully reduced species 2. In this case, subsequent mesolysis would generate the benzyl radical cation G, which would deliver 2 following a HAT step with the DIPEA radical cation D. To confirm whether O-benzoylated species is indeed an intermediate in

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

• triflate 46, alkylation with sulfone 47 via treatment with butyllithium and hexamethylphosphoramide (HMPA) yielded the coupling product 48 as a mixture of diastereoisomers in 60% yield. Ultimately, single-electron reduction removed both the sulfone and benzyl groups of 48, furnishing (S)-α-tocotrienol (49

• , affording monobenzoate 169 in 97% yield with 96% ee. For 2-alkyl-substituted glycerols like triol 167, complex 168 is the most efficient catalyst as the BOX ligand with a benzyl substitution at C4 provided an appropriate size for the catalyst–substrate coordination [58]. The intermediate 169 was transformed

• removal of the benzyl group, chemoselective N-alkylation with fragment 196, and removal of the benzoyl group allowed the conversion of 195 into iodide 197. Sequential oxidation of the alcohol, HWE reaction, and reduction of the resulting ester then provided compound 198. In the presence of Pd(OAc)2, PPh3

Stereoselective electrochemical intramolecular imino-pinacol reaction: a straightforward entry to enantiopure piperazines

• Margherita Gazzotti,
• Fabrizio Medici,
• Valerio Chiroli,
• Laura Raimondi,
• Sergio Rossi and
• Maurizio Benaglia

Beilstein J. Org. Chem. 2025, 21, 1897–1908, doi:10.3762/bjoc.21.147

• photocatalysts (Scheme 2). The combination of photoredox catalysis with imine activation enabled the reductive coupling of imines under mild reaction conditions, providing direct access to benzyl and aryl vicinal diamines with good to excellent yields. Organic electrochemistry represents an attractive and

• for different N-benzyl benzaldimines in moderate to good yields. In 1991, Shono’s research group described the electroreductive intramolecular coupling of aromatic diimines, carried out in DMF in the presence of methanesulfonic acid in a divided cell equipped with a lead cathode, a carbon rod anode

Chiral phosphoric acid-catalyzed asymmetric synthesis of helically chiral, planarly chiral and inherently chiral molecules

• Wei Liu and
• Xiaoyu Yang

Beilstein J. Org. Chem. 2025, 21, 1864–1889, doi:10.3762/bjoc.21.145

• the efficient asymmetric synthesis of inherently chiral eight-membered N-heterocycle 6,7-diphenyldibenzo[e,g][1,4]diazocines (DDDs), which displayed a rigid saddle-shaped configuration [16]. Starting from readily available [1,1'-biphenyl]-2,2'-diamines 62 and benzyl compounds 63, the asymmetric

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

• (37) followed by reduction with Zn/Ba(OH)2 and partial re-oxidation (Scheme 12A) [52]. They can also be obtained from o-halogenated benzyl bromides 40 by lithium–halogen exchange followed by nucleophilic substitution and a second lithium–halogen exchange with iodine (Scheme 12B) or by nickel-catalysed

• reductive cross-coupling of benzyl halides when substituents prone to reduction (CN, esters) are present (Scheme 12C). The Ullman–Goldberg coupling of 41b with Boc-hydrazine followed by deprotection and oxidation then affords 35 [55]. Asymmetric diazocines can be synthesised by Sonogashira cross-coupling

• molybdenum catalyst allows partial conversion of the recovered by-product to the final product 35b, while for the S-heterodiazocine lead was used for the reduction in neat conditions (Scheme 14) [53]. N-Heterodiazocines (Scheme 15) can be synthesised by coupling of monoprotected diamine 55 with benzyl

Convenient alternative synthesis of the Malassezia-derived virulence factor malassezione and related compounds

• Karu Ramesh and
• Stephen L. Bearne

Beilstein J. Org. Chem. 2025, 21, 1730–1736, doi:10.3762/bjoc.21.135

• . 20% (4 steps) relative to an overall yield of ca. 5% via the preparation of the isonitrile followed by the Fe hydride initiated isonitrile–olefin intramolecular coupling reaction [18]. Protection of the indole nitrogens with the Boc group was preferable to the use of benzyl protecting groups since

• removal of the benzyl groups by hydrogenation was problematic (vide infra). The NMR spectral characteristics of the resulting material were identical to those reported for malassezione either isolated from cultures [11][20] or prepared from the isonitrile [18]. To further demonstrate the utility of the

• intent of using the benzyl group to protect the indole nitrogen rather than the Boc group. However, Pd-catalyzed hydrogenation of 25d led to a mixture of products, of which some were consistent with reduction of the indole ring. With respect to the scalability of the synthesis, the reactions can be

Approaches to stereoselective 1,1'-glycosylation

• Daniele Zucchetta and
• Alla Zamyatina

Beilstein J. Org. Chem. 2025, 21, 1700–1718, doi:10.3762/bjoc.21.133

• tetrabenzylated glucose lactol acceptor 2, resulting in the formation of the β,α-1,1-linked diglucoside 3 (Scheme 1) [49]. The application of a the 2,3,4,6-tetra-O-benzyl trichloroacetimidate donor 4 resulted in the same disaccharide product 3, albeit as part of a mixture with other diastereomers [51]. The

• (Scheme 2). Switching from “disarming” ester to “arming” benzyl protecting groups, as in the donor 21, enhanced the activation of the glycosidic center, resulting in the formation of a substantial amount of the methyl glycoside by-product and a reduced yield of the 1,1'-disaccharide 22. Securing the

• groups, as in the imidate donor 29, instead of benzyl ethers, was fully compatible and resulted in the exclusive formation of β-mannosyl-α-glucoside 30 [57]. This approach was successfully applied to the synthesis of a nonreducing disaccharide moiety of evernimicin, an octasaccharide antibiotic that