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

• benzotriazole-adduct formation proceeds poorly with sterically demanding secondary amines and fails with primary amines. However, the latter may be overcome by adding a temporary benzyl group on the amine which can be subsequently cleaved by hydrogenolysis as demonstrated by the authors. Finally, it was shown

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

• abstracts a hydrogen atom from substrate 1 through HAT, producing an α-amido-acridinyl radical intermediate 92 and a substrate-derived carbon-centered radical 4. Radical 4 undergoes regioselective addition to the acceptor, forming transient radical adduct 93. A concomitant SET from 92 to 93 generates a

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

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

• isolated in 77% yield (1.3 g, 4.61 mmol). In order to propose the reaction mechanism, control experiments were conducted (Scheme 4). The reaction is completely inhibited by the addition of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) or BHT (Scheme 4, reaction 1). A BHT-adduct derived from a P-centered

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

• tested, AlCl₃ gave the best result, while CuCl, ZnCl2, PdCl2 and Sc(OTf)3 showed moderate conversions (30–55%), and InCl3 had the lowest efficiency. Without any Lewis acid we observed no conversion by LC–MS (Table 1, entry 16). During the reaction, IMDA adduct 7a was detected by LC–MS (Figure S1

• calculated using the Gaussian 16 software (Figure 3) [21]. The N-acylated compound 6a has a baseline relative energy of 0 kJ/mol, while the transition state of the Diels–Alder (TS-DA) reaction presents the highest energy barrier at 1.221 kJ/mol. The DA adduct shows a little lower energy at 1.001 kJ/mol

Investigations of amination reactions on an antimalarial 1,2,4-triazolo[4,3-a]pyrazine scaffold

• Henry S. T. Smith,
• Ben Giuliani,
• Kanchana Wijesekera,
• Kah Yean Lum,
• Sandra Duffy,
• Aaron Lock,
• Jonathan M. White,
• Vicky M. Avery and
• Rohan A. Davis

Beilstein J. Org. Chem. 2025, 21, 1126–1134, doi:10.3762/bjoc.21.90

• previous reports [10]. A single and identical product was obtained from each reaction and the product, 2, was characterised following analysis of HRESIMS and 1D (1H, 13C) and 2D (COSY, HSQC, HMBC, ROESY) NMR data. The HRESIMS data of 2 showed a Na adduct ion at m/z 372.0991 [M + Na]+ (calcd for

Gold extraction at the molecular level using α- and β-cyclodextrins

• Susana Santos Braga

Beilstein J. Org. Chem. 2025, 21, 1116–1125, doi:10.3762/bjoc.21.89

• that a 2:1 ratio (α-CD to KAuBr4) was sufficient to ensure a co-precipitation yield of 78% and that this value remains relatively constant with increasing amounts of α-CD. It was, thus, concluded that adding extra amounts of α-CD do not help increasing the yield and that the co-precipitated adduct has

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

• styrenes with alkyl formates and the oxidant 4-cyano-1-(1-methylethoxy)pyridinium trifluoromethanesulfonate to give the corresponding cinnamate esters 185–192 via intermolecular addition of styrene to an alkoxyradical forming radical adduct 193 (Scheme 59) [102]. Iwasawa and co-workers (2020) employed CO2

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

• 0.4% amount of cat. 1 provided adduct 30 in 72% yield with 92% enantioselectivity, and the reaction could be scaled up to decagrams. Subsequent decarboxylation and recrystallization of the resulting ketone 31 yielded an enantiopure product (99% ee), which serves as a versatile intermediate for the

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

• instability of α-iodoenone 13. Inspired by the influential studies by Knochel [36] and Baran [48], we discovered that Mg/I exchange of 13 could be accomplished with iPrMgCl·LiCl at −78 °C. The resulting Grignard reagent reacted smoothly with aldehyde 14, affording the corresponding adduct 12 in 58% yield (92

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

• studied silver(I)-catalyzed intramolecular heteroannulation reaction is depicted in Scheme 5. The process begins with the π-coordination of the silver catalyst to the triple bond in the Ugi-adduct 15a generating intermediate A. This is followed by a nucleophilic attack by the pyrazole nitrogen on the

Development and mechanistic studies of calcium–BINOL phosphate-catalyzed hydrocyanation of hydrazones

• Carola Tortora,
• Christian A. Fischer,
• Sascha Kohlbauer,
• Alexandru Zamfir,
• Gerd M. Ballmann,
• Jürgen Pahl,
• Sjoerd Harder and
• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2025, 21, 755–765, doi:10.3762/bjoc.21.59

• that might similarly occur also in related addition reactions of alkenes, for example. After 11E had reacted with TMSCN, adduct 13 forms, 3.8 kcal·mol−1 more stable than the competing unreactive adduct obtained from "Z" conformation. Outside from the catalytic cycle, 12 could be further hydrolyzed in a

• . However, trends in (and even extent of) enantioselectivity are very similar for both kinetic and thermodynamic control for the configuration-determining hydrocyanation step and for both Z- and E-hydrazones, respectively. The replacement step is initiated by forming an adduct 13 from reaction of 11E with

• internal rotation in 11 via TS8 and reaction with TMSCN to give adduct 13 (see Figure 3). Distances and bond lengths are given in pm. Catalyst 7 is replaced in TS 11-12 by concerted electrophilic intramolecular substitution with formal trimethylsilyl cation as electrophile. Please note the surprisingly

Semisynthetic derivatives of massarilactone D with cytotoxic and nematicidal activities

• Rémy B. Teponno,
• Sara R. Noumeur and
• Marc Stadler

Beilstein J. Org. Chem. 2025, 21, 607–615, doi:10.3762/bjoc.21.48

• % yield) obtained as a white powder. Its molecular formula C27H31ClO10 was deduced from the HRESIMS spectrum (Figure S2, Supporting Information File 1), which exhibited the sodium adduct at m/z 573.1495 (calcd. for C27H31ClO10Na+: 573.1498) and NMR analysis. In addition to resonances attributed to

• Information File 1) which showed the protonated molecular ion peak and the sodium adduct at m/z 325.1281 [M + H]+ (calcd. for C16H21O7+: 325.1282) and 347.1103 (calcd. for C16H20O7Na+: 347.1101), respectively. Its 1HNMR spectrum displayed in addition to signals ascribed to massarilactone D, those of a

• the above data, compound 7 was found to be massarilactone D 4-O-crotonyl-7-O-methyl. The HRESIMS of the reaction product 8 (Figure S54, Supporting Information File 1) revealed a protonated molecular ion peak at m/z 379.1383 [M + H]+ and a sodium adduct ion peak at m/z 401.1203 [M + Na]+ corresponding

Formaldehyde surrogates in multicomponent reactions

• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Bernhard Westermann

Beilstein J. Org. Chem. 2025, 21, 564–595, doi:10.3762/bjoc.21.45

• . Application of glyoxylate derivatives in post-cyclization reactions as a C1 building block Glyoxylate derivatives have been used in Ugi- and Passerini-type reactions, since the adduct generated in both cases has two reactive centers for post-cyclization possibilities: the ester moiety and the α-carbon to the

• salts and TEMPO as the radical initiator/oxidant couple that promoted the intramolecular radical cyclization of suitable 1,3-dicarbonyl Ugi adducts 54 and 55 (Scheme 45) [108][109]. The stabilization of the enol in the 1,3-dicarbonyl Ugi adduct allows single-electron transfer (SET) with the anion

• these examples, even if the whole process is performed in one-pot, the reaction needs two steps: the generation of the Ugi (or Passerini) adduct and then the post-cyclization reaction. Interestingly, Peshkov et al. showed that when phenyl glyoxal is used instead of ethyl glyoxylate, a pyrrolone

Organocatalytic kinetic resolution of 1,5-dicarbonyl compounds through a retro-Michael reaction

• James Guevara-Pulido,
• Fernando González-Pérez,
• José M. Andrés and
• Rafael Pedrosa

Beilstein J. Org. Chem. 2025, 21, 473–482, doi:10.3762/bjoc.21.34

• reaction mixture. The percentage of the retro-Michael reaction was calculated by comparing the signal of the starting 1,5-dicarbonyl adduct (rac-1) with the enal (cinnamaldehyde) product of the retro-Michael reaction. To determine whether the reaction favors one stereoisomer over the other and to assess

• are reacted in the presence of the catalyst A [25]. This can be explained by considering the principle of microscopic reversibility. In the reversible process, the catalyst forms the same enamine intermediate preferentially formed in the Michael reaction. This means that the adduct anti-(3R,4S)-1

• favored, preserving the (3S,4R)-1 untransformed and avoiding the equilibrium reversal towards the formation of the Michael adduct, thereby preserving the enantiomeric purity of the isolated product. To investigate the scope of the reaction, we extended our kinetic resolution study to a set of 5

New tandem Ugi/intramolecular Diels–Alder reaction based on vinylfuran and 1,3-butadienylfuran derivatives

• Yuriy I. Horak,
• Roman Z. Lytvyn,
• Andrii R. Vakhula,
• Yuriy V. Homza,
• Nazariy T. Pokhodylo and
• Mykola D. Obushak

Beilstein J. Org. Chem. 2025, 21, 444–450, doi:10.3762/bjoc.21.31

• -3aH-furo[2,3-f]isoindole core in excellent yields. Under the same conditions, the (2E,4E)-5-(furan-2-yl)penta-2,4-dienal gives an Ugi adduct that undergoes the IMDA reaction without involving the furan core. The cycloaddition leads to the formation of 2,3,3a,4,5,7a-hexahydro-1H-isoindoles in high

• the Ugi reaction with a maleic acid to form adducts containing both, diene and dienophilic fragments. It was found that aldehyde 1a reacted with amines 2, isonitriles 3, and maleic acid monoanilide (4a) to form an adduct that spontaneously underwent a [4 + 2] cycloaddition giving furoisoindoles 5a–h

• achieving molecular diversity of derivatives for creating libraries of compounds for bioscreening. Finally, in such a tandem Ugi/IMDA reaction, furyl-2-pentadienal was studied. It was found, that the Ugi adduct formed from (2E,4E)-5-(furan-2-yl)penta-2,4-dienal (8) underwent the IMDA reaction, without

Antibiofilm and cytotoxic metabolites from the entomopathogenic fungus Samsoniella aurantia

• Rita Toshe,
• Syeda J. Khalid,
• Blondelle Matio Kemkuignou,
• Esteban Charria-Girón,
• Paul Eckhardt,
• Birthe Sandargo,
• Kunlapat Nuchthien,
• J. Jennifer Luangsa-ard,
• Till Opatz,
• Hedda Schrey,
• Sherif S. Ebada and
• Marc Stadler

Beilstein J. Org. Chem. 2025, 21, 327–339, doi:10.3762/bjoc.21.23

• (Figure 1) was purified as a yellow amorphous solid. The molecular formula of 1 was determined as C25H29NO5 indicating twelve degrees of unsaturation based on the HRESIMS that revealed a protonated molecule at m/z 424.2126 [M + H]+ (calculated 424.2118) and a sodium adduct at m/z 446.1947 [M + Na

Three-component reactions of conjugated dienes, CH acids and formaldehyde under diffusion mixing conditions

• Dmitry E. Shybanov,
• Maxim E. Kukushkin,
• Eugene V. Babaev,
• Nikolai V. Zyk and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2025, 21, 262–269, doi:10.3762/bjoc.21.18

• formaldehyde (generated from paraformaldehyde upon heating), an adduct of a methylidene derivative of a CH acid dienophile was detected in some cases only in reference [15] (when carrying out the reaction in a sealed tube in the presence of copper(II) acetate). However, in most reactions only the hetero-Diels

• and 8, the reaction also produced hetero-Diels–Alder reaction adducts 6 and 9. For these, CH–O 1H NMR signals in the region of 4.9–5.4 ppm were characteristic. It is worth noting that the individual isolated compounds 8 and particularly 9 were unstable when stored in solution, and boiling adduct 8 or

Dioxazolones as electrophilic amide sources in copper-catalyzed and -mediated transformations

• Seungmin Lee,
• Minsuk Kim,
• Hyewon Han and
• Jongwoo Son

Beilstein J. Org. Chem. 2025, 21, 200–216, doi:10.3762/bjoc.21.12

• amidation process of dioxazolones. Dioxazolone 1 binds to the chiral copper complex 3, generating the adduct INT-1. Decarboxylation then occurs, forming the copper nitrenoid intermediate INT-2, subsequently undergoing hydrogen atom transfer in a regioselective manner to afford INT-3. The related acyl

Quantifying the ability of the CF₂H group as a hydrogen bond donor

• Matthew E. Paolella,
• Daniel S. Honeycutt,
• Bradley M. Lipka,
• Jacob M. Goldberg and
• Fang Wang

Beilstein J. Org. Chem. 2025, 21, 189–199, doi:10.3762/bjoc.21.11

• the HB donor. As shown in Figure 3B, in our hands, the Kd of the phenol–Reichardt's dye HB adduct determined is consistent with the reported value [52]. Some of our other results, however, were puzzling. For example, according to our titration data, 1a is a better HB donor than 12. This observation is

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

• that benzofuran adduct 15c was previously reported by Dyker to be obtained in only 10% yield when 12 was reacted with 10 equivalents of unsubstituted benzofuran, in the presence of 5 mol % of Pd(OAc)2 at 100 °C for 3 days [52]. The compatibility of five-membered nitrogen heterocycles with our

Direct trifluoroethylation of carbonyl sulfoxonium ylides using hypervalent iodine compounds

• Radell Echemendía,
• Carlee A. Montgomery,
• Fabio Cuzzucoli,
• Antonio C. B. Burtoloso and
• Graham K. Murphy

Beilstein J. Org. Chem. 2024, 20, 3182–3190, doi:10.3762/bjoc.20.263

• reductive elimination (path 1) [37][38][39]. This pathway initiates by formation of a halogen bond complex between 1a and the trifuoroethyl(mesityl)iodonium ion 2a’, where adduct XB-1 is presumably in equilibrium with isomeric XB-2. Reductive elimination of the iodoarene from XB-2 would furnish B, whose

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• , isocyanide, and TMSN3, after which the Ugi adduct is treated with an excess of different isocyanates resulting in the corresponding hydantoin derivatives. Finally, under microwave irradiation, the Boc group is removed under acid conditions and the benzodiazepine core is formed after ring closure (Scheme 18

• agents for central nervous system pathologies. This combination not only enhances the pace of discovery but also broadens the scope of potential treatments, underscoring the significant impact of MCRs in medicinal chemistry. Classical MCRs. Different scaffolds that can be formed with the Ugi adduct. Most

Hypervalent iodine-mediated intramolecular alkene halocyclisation

• Charu Bansal,
• Oliver Ruggles,
• Albert C. Rowett and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 3113–3133, doi:10.3762/bjoc.20.258

• , deuterium labelling, rearrangements on stereodefined substrates, and structural analyses (NMR and X-ray) of the reaction products. RT-NMR-derived data strongly supported a pathway of alkene activation by the iodane, as opposed to the formation of an N-I(III) adduct. The presence of 5-exo-products, with

• . A mechanism for the reaction was proposed by the authors (Scheme 27), whereby a TMS-adduct A of the amide is formed, alkene activation and cyclisation from oxygen forms the cyclised intermediate B, then displacement of PhI by chloride gives the product. Chai, Jiang, Zhu and co-workers reported the

Advances in the use of metal-free tetrapyrrolic macrocycles as catalysts

• Mandeep K. Chahal

Beilstein J. Org. Chem. 2024, 20, 3085–3112, doi:10.3762/bjoc.20.257

• (Table 5). DFT calculations predicted that the catalytically active species is the adduct of porphyrin and TBACl (18-I), which forms an activated complex (18-II) with the substrate followed by a ring-opening nucleophilic attack of Cl−. The electron-rich nitrogen atom in 18-III further activates

• porphyrins, and provided evidence for aryl radical formation through mass spectrometry and NMR analysis of the adduct formed from the reaction between the radical intermediate and the scavenger 2,2,6,6-tetramethyl-1-piperidin-1-oxyl (TEMPO). Furthermore, they used the catalysts for borylation of arylamines