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

• , amides or esters and occurs under very mild conditions that are also suitable for a late-stage functionalisation of complex molecules. The transformation is based on an H-atom transfer to photochemically oxidised quinuclidine followed by an annulation of the resulting ketyl radical 32 with

• enantioselectivities. In 2018, Scheidt and colleagues disclosed the first N-heterocyclic carbene (NHC)-catalysed [2 + 2] annulation between trifluoromethyl ketones and γ-substituted allenoates (Scheme 25a) [68]. The resulting 2-alkylideneoxetane products 95 were generally obtained in >90% yields and good

• -catalysed heterocycle synthesis, specifically a [3 + 2] annulation of 3-(4-hydroxyphenyl)oxetan-3-ol (211) with β-naphthylamines or phenols 210 to give benzoindolines and 2,3-dihydrobenzofurans 212, respectively (Scheme 50) [104]. The reaction gave moderate to high yields and control experiments indicated

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

• CHCl3, AcOH and o-DCB [44]. The resulting mixture of brominated PAHs 30 and 31 was then subjected to single or double [3 + 2] annulation with various alkynes, leading to the extended structures 32 and 33. Notably, compound 33d can undergo Pd-catalysed dimerization, resulting in the formation of a chiral

• characteristics to most azulene-embedded PAHs obtained via Scholl oxidation – specifically, the azulene subunit does not exhibit aromaticity, and the surrounding benzenoid rings predominantly determine the electronic structure of 49. [3 + 2] Annulation of alkynes accompanied by a phenyl ring expansion: The

• 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

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

• to the formation of radical annulation species 59. Single-electron oxidation and deprotonation then take place, resulting in the final cyclized products 56a. N-Arylalkenes: α-carbonyl alkyl C(sp3)-centered radicals In 2014, Li’s group developed an oxidative difunctionalization of N-arylacrylamides

• olefinic carbonyls with α-bromoalkylcarbonyls promoted by tert-butyl hydroperoxide (TBHP) and Et3N was developed by Li’s group in 2019 (Scheme 31) [19]. The reaction relied on a Ag-catalyzed concomitant intramolecular annulation process, and presented a broad substrate scope, excellent levels of

• photocatalyst's efficiency in mediating both the initiation and propagation steps of the radical cascade annulation. In 2023, Huang and his research group documented a visible-light-induced photoredox PCET/SCS cascade cyclization process to deliver functionalized acyloxindoles with good to excellent yields. In

A multicomponent reaction-initiated synthesis of imidazopyridine-fused isoquinolinones

• Ashutosh Nath,
• John Mark Awad and
• Wei Zhang

Beilstein J. Org. Chem. 2025, 21, 1161–1169, doi:10.3762/bjoc.21.92

• reaction followed by the cleavage of the alkyl group to give intermediate II as a free amine. Annulation of II with CDI gave product B which is an HIV reverse transcriptase inhibitor (Scheme 1B) [17]. We have reported a three-component [3 + 2] cycloaddition followed by IMDA reaction for making heterocyclic

Salen–scandium(III) complex-catalyzed asymmetric (3 + 2) annulation of aziridines and aldehydes

• Linqiang Wang and
• Jiaxi Xu

Beilstein J. Org. Chem. 2025, 21, 1087–1094, doi:10.3762/bjoc.21.86

• moieties of biologically active compounds. A salen–scandium triflate complex-catalyzed asymmetric (3 + 2) annulation of dialkyl 1-sulfonylaziridine-2,2-dicarboxylates and aldehydes generated optically active functionalized oxazolidine derivatives in moderate to good yields and good to excellent

• enantioselectivities and high diastereoselectivities. A reasonable reaction mechanism was proposed and rationalized the experimental results. Keywords: aldehyde; annulation; aziridine; oxazolidine; ring expansion; scandium triflate; Introduction Oxazolidine derivatives are an important class of nitrogen and oxygen

• alcohols and aldehydes [11] and through [2 + 3] cycloaddition of azomethine ylides and carbonyl dipolarophiles [12]. Recently, the [2 + 3] annulation of aldehydes and donor–acceptor dialkyl 2-aryl-1-sulfonylaziridine-2,2-dicarboxylates, which generate azomethine ylides, has been developed for the synthesis

Recent total synthesis of natural products leveraging a strategy of enamide cyclization

• Chun-Yu Mi,
• Jia-Yuan Zhai and
• Xiao-Ming Zhang

Beilstein J. Org. Chem. 2025, 21, 999–1009, doi:10.3762/bjoc.21.81

• cyclization modes that provide entries to various N-heterocycles, some of which serve as key structural motifs in natural alkaloids. This review highlights recent advancements in enamide-based cyclization reactions, including enamide–alkyne cycloisomerization, [3 + 2] annulation, and polycyclization, with a

• triggered a Grob fragmentation process of hemiaminal 16 and afforded the imide compound 17. Final regioselective reduction of one of the two carbonyls on the imide completed the synthesis of (−)-phlegmariurine B. Annulation Total syntheses of cephalotaxine and cephalezomine H The [2 + 3] annulation of

• annulation and applied it in the divergent total synthesis of Cephalotaxus alkaloids (Scheme 3) [22], including cephalotaxine whose ester, homoharringtonine, has been listed as an approved FDA drug for the treatment of chronic myeloid leukemia [23]. In their elegant study, an Au-catalyzed [2 + 3] annulation

A convergent synthetic approach to the tetracyclic core framework of khayanolide-type limonoids

• Zhiyang Zhang,
• Jialei Hu,
• Hanfeng Ding,
• Li Zhang and
• Peirong Rao

Beilstein J. Org. Chem. 2025, 21, 926–934, doi:10.3762/bjoc.21.75

• oxidative truncation of apotirucallane or apoeuphane precursors coupled with subsequent β-furan annulation [1][2][3][4][5][6], constitute an architecturally sophisticated family of natural products. Based on their specific skeletal rearrangements, limonoids can be systematically categorized into four

Silver(I) triflate-catalyzed post-Ugi synthesis of pyrazolodiazepines

• Muhammad Hasan,
• Anatoly A. Peshkov,
• Syed Anis Ali Shah,
• Andrey Belyaev,
• Chang-Keun Lim,
• Shunyi Wang and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2025, 21, 915–925, doi:10.3762/bjoc.21.74

• . Another set of pyrazolodiazepines 16p–v was readily obtained from the substrates 15p–v stemming from various 3-substituted propiolic acids and aliphatic or aromatic isocyanides. Finally, the annulation of substrates 15w and 15x, featuring a terminal alkyne, also proceeded in a 7-endo-dig fashion, yielding

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

• reactivity of cyclic diazo imides and mechanism [40]. Palladium-catalyzed annulation of prochiral N-arylphosphonamides with aromatic iodides [41]. Time-dependent enantiodivergent synthesis [42]. Time-controlled palladium-catalyzed divergent synthesis of silacycles via C–H activation [43]. Proposed mechanism

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

• reactivity of the diazonium salt. When strong electron-withdrawing groups (EWGs) were introduced, the yield was also reduced, likely due to the low nucleophilicity of the aniline derivative and the ineffective formation of a diazonium salt. An annulation reaction of compound 2 was performed with either

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

• phenyl rings' ortho, meta, or para positions. This method proceeded via an anodic oxidation, followed by intramolecular cyclization (Scheme 32). The key role of anodic oxidation became evident when the annulation product

New advances in asymmetric organocatalysis II

• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 766–769, doi:10.3762/bjoc.21.60

• , carbohydrates, or thiourea [5][6][7][8]. Going even more back in time, we shall recognize the work of Eder, Sauer, Wiechert, Hajos, and Parrish on the proline-catalyzed Robinson annulation in the 1970s [9][10]. In light of this, organocatalysis appears to be 50 rather than 25 years old. But is even that correct

Molecular diversity of the reactions of MBH carbonates of isatins and various nucleophiles

• Zi-Ying Xiao,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2025, 21, 286–295, doi:10.3762/bjoc.21.21

• ]. In the presence of a Lewis base, MBH carbonates of isatins can be easily converted to activated allylic ylides, which in turn can undergo allylic substitution and annulation reactions to give diverse 3-substituted and spirooxindole derivatives [36][37][38][39][40][41]. Inspired by these elegant

• and were fully characterized via various spectroscopy methods. The further annulation reaction did not proceed under the reaction conditions. The similar reaction of triphenylphosphine and MBH maleimides of isatins also resulted in the corresponding triphenylphosphaneylidenes 6e and 6f in satisfactory

Synthesis of disulfides and 3-sulfenylchromones from sodium sulfinates catalyzed by TBAI

• Zhenlei Zhang,
• Ying Wang,
• Xingxing Pan,
• Manqi Zhang,
• Wei Zhao,
• Meng Li and
• Hao Zhang

Beilstein J. Org. Chem. 2025, 21, 253–261, doi:10.3762/bjoc.21.17

• presented above, the substrate range of the TBAl-catalyzed sulfenylation/annulation reaction between different arylated enaminones and sodium p-tolylsulfinate was subsequently investigated, and the corresponding results are shown in Scheme 3. From the results, both electron-withdrawing and electron-donating

Heteroannulations of cyanoacetamide-based MCR scaffolds utilizing formamide

• Marios Zingiridis,
• Danae Papachristodoulou,
• Despoina Menegaki,
• Konstantinos G. Froudas and
• Constantinos G. Neochoritis

Beilstein J. Org. Chem. 2025, 21, 217–225, doi:10.3762/bjoc.21.13

• moiety of the amide group resulted in pyrimidone annulation [41]. This was observed for the first time and completed the reported heteroannulation landscape utilizing the Niementowski reaction [25]. In general, the reactions had a rather broad scope as a great range of cyanoacetamides was compatible. The

Recent advances in electrochemical copper catalysis for modern organic synthesis

• Yemin Kim and
• Won Jun Jang

Beilstein J. Org. Chem. 2025, 21, 155–178, doi:10.3762/bjoc.21.9

• Cu-catalyzed electrochemical C–H activation strategy through C–H alkynylation of arylamides followed by electrooxidative cascade annulation (Figure 4) [48]. This reaction enables sustainable C–H functionalization by utilizing electricity as the terminal oxidant instead of stoichiometric amounts of

• desired annulation products. Moreover, the same products were generated using alkynyl carboxylic acids instead of terminal alkynes via decarboxylative C–H alkynylation and annulation. Cyclic voltammetry (CV) studies exhibited an oxidative current at 0.95 V vs SCE in the presence of the Cu(II) salt, base

• (KR) of the racemic ketimine ester, providing the same chiral product 35 with recovered enantioenriched starting material. Additionally, when a 1-naphthyl ester was used instead of a methyl ester at −10 °C, 1,4-addition followed by intramolecular tandem annulation generated the corresponding chiral

Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• the coupling with copper triflate as catalyst, without ligand, co-catalyst or other additives. The reaction involved the formation of the imine XVII followed by alkynylation to propargylamine XVIII, cyclization, and oxidation to quinoline 23 (Scheme 17) [34]. Three component oxidative annulation to

• -methylthiazole-2-carboxaldehyde as chelating agent, in the presence of copper triflate and the chiral diamine ligand 28. The stereoselectivity was directed by the formation of a proposed catalyst complex 29 involving two molecules of Schiff base (Scheme 22) [39]. The three-component annulation of aldehydes

Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

• ) annulation of enals with ynamides 8 to afford axially chiral 7-arylindolines 9 was reported [20]. The reaction mechanism, rationalized by DFT calculations, is believed to occur through catalyst C3 activation of the substrate 8, dehydration, and deprotonation with tautomerization leading to the enamine

• -catalyzed (3 + 3) annulation [29]. A broad scope was demonstrated, comprising more than 50 diversely substituted compounds (Scheme 10). Wong, Zhao, and co-workers disclosed the intriguing formation of bridged biaryls featuring eight-membered lactone rings 32 [30]. This serendipitously discovered

• followed by lactonization to Int-21 and Int-22 (Scheme 11c). Chi and co-workers showed that desymmetrization of urazoles can lead to axially chiral derivatives [31]. The NHC-catalyzed (3 + 2) annulation between α,β-unsaturated aldehydes 36 and urazoles 37 generates atropoisomers 38 with a C–N stereogenic

Synthesis of acenaphthylene-fused heteroarenes and polyoxygenated benzo[j]fluoranthenes via a Pd-catalyzed Suzuki–Miyaura/C–H arylation cascade

• Merve Yence,
• Dilgam Ahmadli,
• Damla Surmeli,
• Umut Mert Karacaoğlu,
• Sujit Pal and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2024, 20, 3290–3298, doi:10.3762/bjoc.20.273

• -catalyzed annulation reaction between bromo-chloronaphthalene dicarboximides 6 and heteroarylboronic esters that enabled the syntheses of acenaphthylene-fused thiophene and indole derivatives 7 having donor-acceptor units (Scheme 1a) [40]. In 2021, Jin and co-workers developed an elegant Pd-catalyzed

• reaction cascade starting from diarylalkynes 8, which involves indole formation/peri-C–H annulation and N-dealkylation reactions to afford acenaphthylene-fused indole products 9 (Scheme 1b) [41]. Recently, Takeuchi and co-workers reported an effective Ir-catalyzed [2 + 2 + 2] cycloaddition between 1,8

Efficient synthesis of fluorinated triphenylenes with enhanced arene–perfluoroarene interactions in columnar mesophases

• Yang Chen,
• Jiao He,
• Hang Lin,
• Hai-Feng Wang,
• Ping Hu,
• Bi-Qin Wang,
• Ke-Qing Zhao and
• Bertrand Donnio

Beilstein J. Org. Chem. 2024, 20, 3263–3273, doi:10.3762/bjoc.20.270

• subsequent second annulation, yielding a new series of extended polyaromatic mesomorphic compounds, i.e., 1,1',3,3',4,4'-hexafluoro-6,6',7,7',10,10',11,11'-octaalkoxy-2,2'-bitriphenylene (Gnm) which were found to display a Colrec mesophase. The specific nucleophilic substitution patterns of the Fn

• enables to exploit further the SNFAr procedure, as demonstrated for 4F-TPn and 6F-BTPn [44], through a subsequent second annulation reaction. This results in a second series of extended π-conjugated aromatic mesomorphic compounds, 1,1',3,3',4,4'-hexafluoro-6,6',7,7',10,10',11,11'-octaalkoxy-2,2

• prepared in high yield via FeCl3-oxidative coupling of 1,2-dialkoxy-4-bromobenzene (Scholl reaction). The new triphenylene derivatives, F3–F12, were prepared in moderate to high yields (51–73%). In addition, three bitriphenylene derivatives were synthesized in a subsequent annulation step from Fn

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• evaluate the synthetic utility of this methodology, derivative 39e was reduced using BF3·OEt2 and Et3SiH leading to 41 in a good yield and moderate diastereoselectivity (Scheme 14). In 2017, Li’s group developed a chiral (DHQ)2PHAL-catalyzed [2 + 4] annulation reaction of cyclic 1-azadiene 14 with γ-nitro

• Mannich-type reaction of isocyanoacetates with N-(2-benzothiazolyl)imines. Enantioselective modified cinchona alkaloid-catalyzed [4 + 2] annulation of γ-butenolides and saccharin-derived 1-azadienes. Chiral tertiary amine-catalyzed [2 + 4] annulation of cyclic 1-azadiene with γ-nitro ketones. Inverse

Synthesis of the 1,5-disubstituted tetrazole-methanesulfonylindole hybrid system via high-order multicomponent reaction

• Cesia M. Aguilar-Morales,
• América A. Frías-López,
• Nadia V. Emilio-Velázquez,
• Alejandro Islas-Jácome,
• Angelica Judith Granados-López,
• Jorge Gustavo Araujo-Huitrado,
• Yamilé López-Hernández,
• Hiram Hernández-López,
• Luis Chacón-García,
• Jesús Adrián López and
• Carlos J. Cortés-García

Beilstein J. Org. Chem. 2024, 20, 3077–3084, doi:10.3762/bjoc.20.256

• , 98160, México 10.3762/bjoc.20.256 Abstract A series of 1,5-disubstituted tetrazole-indole hybrids were synthesized via a high-order multicomponent reaction consisting of an Ugi-azide/Pd/Cu-catalyzed hetero-annulation cascade sequence. This operationally simple one-pot protocol allowed high bond-forming

Synthesis of pyrrole-fused dibenzoxazepine/dibenzothiazepine/triazolobenzodiazepine derivatives via isocyanide-based multicomponent reactions

• Marzieh Norouzi,
• Mohammad Taghi Nazeri,
• Ahmad Shaabani and
• Behrouz Notash

Beilstein J. Org. Chem. 2024, 20, 2870–2882, doi:10.3762/bjoc.20.241

• -workers reported a one-pot three-component reaction (3-CR) of sulfamate‐derived cyclic imine, isocyanide, and acetylenedicarboxylate. In this reaction too, the pyrrole-fused sulfamate is synthesized through intermediacy of the in situ-formed zwitterion II and [1 + 2 + 2] annulation reaction (Scheme 1b

C–C Coupling in sterically demanding porphyrin environments

• Liam Cribbin,
• Brendan Twamley,
• Nicolae Buga,
• John E. O’ Brien,
• Raphael Bühler,
• Roland A. Fischer and
• Mathias O. Senge

Beilstein J. Org. Chem. 2024, 20, 2784–2798, doi:10.3762/bjoc.20.234

• ’ steric demand as seen with compound 11 with opposing bromines, coupled with the added complication of being a rotameric mixture, as well as adjacent hindrance of the nearby β-ethyl groups. Examples of palladium coupling on ‘opposing’ halogen atoms can be seen in the annulation of vic-bis(pinacolatoboryl

Copper-catalyzed yne-allylic substitutions: concept and recent developments

• Shuang Yang and
• Xinqiang Fang

Beilstein J. Org. Chem. 2024, 20, 2739–2775, doi:10.3762/bjoc.20.232

• reaction. Therefore, they believe that the dearomatization caused by copper vinyl allenylidene intermediate remains a key step in the reaction (Scheme 30). Copper-catalyzed yne-allylic substitution–annulation reactions In the pioneering report [62], Fang et al. found that when cyclic 1,3-dicarbonyls such

• + 2] cyclization of yne-allylic esters and 2-naphthalenols, resulting in a range of allenyl dihydronaphthofuran products with high diastereo- and enantioselectivities (Scheme 34, 32a–h). The attempt to separate the intermediate before cyclization failed, indicating that the following annulation and

• ). Preliminary mechanistic studies have ruled out the 1,3-sigmatropic shift, indicating that the reaction proceeds through a nucleophilic substitution–annulation process of a reactive π-extended copper-allenylidene intermediate (Scheme 43). At the same time, Qi and Xu et al. [79] also realized the dearomative