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

• stable isosteric replacements for gem-dimethyl and carbonyl groups. This work reviews possible synthetic strategies towards these strained heterocycles, covering both de novo constructions of the 4-membered ring as well as derivatisations of oxetane building blocks, then reactivity of oxetanes in terms

• base [5]. In fact, its hydrogen-bond-accepting ability is even stronger than that of the other 3-, 5- and 6-membered cyclic ethers, as well as the carbonyls of aldehydes, ketones, esters and carbonates [6][7][8]. The only better carbonyl-based hydrogen-bond acceptors are amides, carbamates and ureas [9

• ]. The first to recognise that these unique physicochemical properties may have valuable applications in medicinal chemistry were Carreira, Rogers-Evans, Müller and colleagues, who together reported that 3-substituted oxetanes can serve as isosteric replacements for carbonyl and gem-dimethyl groups

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

• -/trifluoroalkylation reagents, α-carbonyl alkyl bromides/alcohols, alkyl halides, and alkyl carboxylic acids, have been successfully applied to this transformation to afford 3-substituted indolin-2-ones. In 2013, Li’s group reported a novel DTBP(di-tert-butyl peroxide)-mediated oxidative 1,2-alkylarylation of

• 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

• selectivity, and high functional group compatibility (65a–f). In 2024, Huang, Liu, and Li’s group introduced a novel approach for the photochemical radical cascade 6-endo cyclization of dienes using α-carbonyl bromides, as illustrated in Scheme 32 [20]. This method is characterized by a visible-light-induced

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

• precursors of α-substituted carbonyl compounds that have been recently applied as coupling partners for radical functionalization with the formation of C–C [63][64][65][66] and C–Het [67][68][69][70] bonds. The ready availability of enol acetates from the corresponding carbonyl compounds in just one

• reactions leading to the corresponding unfunctionalized carbonyl compounds. To date, only the Xu group reported oxidative phosphorylation of enol acetates with dialkyl H-phosphonates and Mn(acac)3 as an oxidant (Scheme 1b) [71]. However, the reported approach is limited by an excess of manganese salt, long

Enhancing chemical synthesis planning: automated quantum mechanics-based regioselectivity prediction for C–H activation with directing groups

• Julius Seumer,
• Nicolai Ree and
• Jan H. Jensen

Beilstein J. Org. Chem. 2025, 21, 1171–1182, doi:10.3762/bjoc.21.94

• resulted in more specific SMARTS patterns matching the DG. For example, Figure 3a shows the result from Tomberg et al. [9], which does not include the carbonyl oxygen in the SMARTS pattern match although the pattern marked in red in Figure 3b is part of the database. This example also highlights that 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

• intermediate 7, the carbonyl oxygen interacts with AlCl₃, enhancing the electrophilicity and promoting the rearrangement to form stable oxonium ions. The removal of water from 7 is facilitated by protonation, producing reactive carbocations which undergo dehydrative aromatization to produce products 8

Supramolecular assembly of hypervalent iodine macrocycles and alkali metals

• Krishna Pandey,
• Lucas X. Orton,
• Grayson Venus,
• Waseem A. Hussain,
• Toby Woods,
• Lichang Wang and
• Kyle N. Plunkett

Beilstein J. Org. Chem. 2025, 21, 1095–1103, doi:10.3762/bjoc.21.87

• lithium tetrakis(pentafluorophenyl)borate ethyl etherate LiBArF20 and sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate NaBArF24. The electron-rich, outwardly projected carbonyl oxygens of the HIM co-crystalize with the cations into bent supramolecular architectures. Both crystal structures show a

• protocol, and the characterization data are consistent with the original dataset [18]. Through a series of crystallographic experiments, we demonstrate that HIMs coordinate with alkali metals through the periphery carbonyl oxygens via metal–oxygen bonding to form a higher order metal-coordinated

• projecting outward denoted by an asterisk. Furthermore, the resulting crystal structure reveals that 1 is also a distorted planar macrocyclic system consisting of the amino acids carbonyl oxygens facing inside the ring. All three benzyl groups are located above a single plane (more figures are provided in

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

• 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 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

• ) utilized isothiocyanate and cinnamic acid (7) to prepare the corresponding amide 47 in good yield via a carbamothioic anhydride 74 formation followed by carbonyl sulfide (COS) release (Scheme 24A) [59]. Similarly, Zhao and co-workers (2020) employed tetraalkylthiuram disulfides to synthesize amides via COS

• yield. The reaction proceeds via a CeO2-coordinated carboxylate mode (Scheme 31A) [67]. In addition, the catalyst also offered high reusability for up to 4 runs thus further promoting the eco-friendliness. Carbonyl activation via Lewis acid–O=C interaction has also been achieved using other transition

• (CO)12, to catalyze the alkyne hydrocarbonylation using CO and ZrF4 as the co-catalyst. The reaction afforded the corresponding amides 133, 277, and 278 in good yields via acyl carbonyl iron intermediate 280, which was observed by NMR (Scheme 69) [118]. By applying less toxic and safer CO2 instead of

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

• first report by Stork in the 1950s [1][2][3]. Compared with enols, enamines benefit from the lone pair of electrons on the nitrogen atom, which enhances the nucleophilicity of the alkene, enabling it to react with a broad range of electrophiles. This activation mode of carbonyl compounds has been so

Studies on the syntheses of β-carboline alkaloids brevicarine and brevicolline

• Benedek Batizi,
• Patrik Pollák,
• András Dancsó,
• Péter Keglevich,
• Gyula Simig,
• Balázs Volk and
• Mátyás Milen

Beilstein J. Org. Chem. 2025, 21, 955–963, doi:10.3762/bjoc.21.79

• described in the literature for trifluoroacetylation of aromatic ring systems with TFA [44][45]. Nevertheless, in our case, trifluoroacetylation of the pyrrole moiety of 30 by TFA and reduction of the carbonyl group of 33 with NaCNBH3 took place in one pot, which is unprecedented in the literature. It is

Harnessing tethered nitreniums for diastereoselective amino-sulfonoxylation of alkenes

• Shyam Sathyamoorthi,
• Appasaheb K. Nirpal,
• Dnyaneshwar A. Gorve and
• Steven P. Kelley

Beilstein J. Org. Chem. 2025, 21, 947–954, doi:10.3762/bjoc.21.78

• (Scheme 3A). The mesylate could be cleanly substituted with azide by heating substrate with excess NaN3 in DMSO (Scheme 3B). With an excess of Schwartz’s reagent, the carbonyl was cleanly reduced to give 1,3-oxazine 62. Contrary to what we had initially predicted from literature precedent, there was no

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

• at C10 was then introduced via a Michael addition (MeMgBr, CuI) to afford 22 in a yield of 65% (4:1 dr at C10). Initial attempts on the carbonyl 1,2-transposition protocol reported by Dong and co-workers were ineffective [45], leading to premature hydride termination and the formation of alkene 23

• single product, with no detection of 34 (Table 1, entry 11). This result presumably arises from the minimization of dipole–dipole repulsions between the carbonyl of the dienone moiety and the C14-OMe within the desired transition state (more details were discussed in our group’s previous work [29

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

• [20][21][22][23]. For example, the Ugi four-component reaction (U4CR), involving a carbonyl compound, a primary amine, a carboxylic acid, and an isocyanide, provides a straightforward method for constructing dipeptide-like adducts [24][25][26][27]. These adducts can subsequently be rigidified into

• carboxylic acid component 3 and additional keto-carbonyl group in aryl glyoxal 1. This approach was further advanced by Ding's group to produce a broader range of benzodiazepines with diverse substitution patterns by shuffling the necessary functional groups within the Ugi reaction components [34][35][36

• intramolecular condensation with the arylglyoxal-derived keto-carbonyl group [37]. In 2024, the same group streamlined this strategy by utilizing unprotected anthranilic acids, enabling the assembly of benzo[e][1,4]diazepines 6 directly during the Ugi reaction step [38]. In 2013, Van der Eycken and co-workers

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

• ) and (3 + 2) cyclization strategies. Two distinct pathways were established: (1) The titanium-catalyzed ring opening of bicyclobutane (BCB) 32 generates a γ-carbonyl radical intermediate Int-42, which undergoes trapping by vinylazide 33. Subsequent dinitrogen extrusion produces an iminyl radical

• –acceptor BCB via Sc(OTf)3 coordination to its carbonyl group facilitates nucleophilic attack by vinylazide 33, forming an imino-diazonium intermediate Int-40 accompanied by a δ-carbanion. Transannular cyclization of this species affords 2-azidobicyclo[3.1.1]hexane (2-azidoBCHs). Subsequent thermal

• reduced electrophilicity of the ester carbonyl. In 2021, Dong and Xie reported the development of an azido Matteson reaction, which achieves carbene insertion into an N–B bond of aminoboranes 84 or 86 (Scheme 22) [53]. In this methodology, by controlling the carbene leaving group (alkyl chlorides/alkyl

Light-enabled intramolecular [2 + 2] cycloaddition via photoactivation of simple alkenylboronic esters

• Lewis McGhie,
• Hannah M. Kortman,
• Jenna Rumpf,
• Peter H. Seeberger and
• John J. Molloy

Beilstein J. Org. Chem. 2025, 21, 854–863, doi:10.3762/bjoc.21.69

• contributions have enabled the efficient activation of carbonyl and alkene moieties, the inability of most organic molecules to efficiently absorb photons at longer wavelengths often preclude their use in direct excitation strategies, requiring unique experimental set ups and light sources that are

Unraveling cooperative interactions between complexed ions in dual-host strategy for cesium salt separation

• Zhihua Liu,
• Ya-Zhi Chen,
• Ji Wang,
• Qingling Nie,
• Wei Zhao and
• Biao Wu

Beilstein J. Org. Chem. 2025, 21, 845–853, doi:10.3762/bjoc.21.68

• carbonyl (C=O) groups, as well as direct ion-pairing interactions between 18-crown-6-complexed Cs+ and hexaurea-bound PO43−. Single-crystal structural analysis corroborates these interactions, shedding light on the underlying mechanisms and providing valuable guidance for the rational design of advanced

• , only two examples provide clear evidence of cooperative interactions based on single crystal structures [28][29], where the 18-crown-6 complexed K+ cation forms ion-dipole interactions with the carbonyl (C=O) or nitro (NO2) groups of the anion-bound receptors (KF and K2CO3). Recently, we demonstrated

• ion-dipole interaction of the Li+ cation and carbonyl groups also contribute to the extraction. The negative electrostatic potential (δ−) of O=C is attributed to a high dipole moment of the urea unit (mono(urea): 3.95 D, bis(urea): 7.55 D) [34][35][36], which has been demonstrated to be capable of

4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches

• Nguyen Tran Nguyen,
• Vo Viet Dai,
• Luc Van Meervelt,
• Do Thi Thao and
• Nguyen Minh Thong

Beilstein J. Org. Chem. 2025, 21, 817–829, doi:10.3762/bjoc.21.65

• forms 3a’–e’ will be attacked by methylamine (4) to yield the tetrahedral intermediate 6 and then, the intramolecular proton transfer will lead to intermediate 7. It has been proven that Schiff’ bases show normally higher reactivity than the corresponding carbonyl compounds towards nitrogen-containing

• nucleophiles [24]. Therefore, it is reasonable that the transimination reaction between 3a’–e’ and 4 preferentially takes place at the carbon atom of the imine (C=N) linkage instead of the carbonyl carbons at the 2- or 3-positions. Lastly, the covalent bond between the tetrahedral carbon atom and the

• a dihedral angle of 49.86(10) 86.22(11)° with the phenyl rings C6–C11 and C18–C23, respectively. The angle between both phenyl rings is 70.76(11)°. The stereochemistry around the double bond is Z, allowing an intramolecular N–H···O hydrogen bond between one of the carbonyl oxygen atoms and the amino

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

• carbonyl group. The halide salts did not lead to product formation, indicating that chloride and bromide anions cannot generate the corresponding radicals to accelerate the conversion of diphenylphosphine. The reaction yield decreased when the methyl group was placed in ortho-position. Moreover, the

• corresponding phosphorylated propargyl alcohols (Scheme 19). The reaction yield showed that this method is not sensitive to electron-withdrawing or electron-donating groups at different positions on the aromatic ring. Most likely, the 3-substituted pyridine substrate and the enynes with nitro or carbonyl groups

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

• through calcium catalysis [8][9][10]. Asymmetric synthesis has also been achieved via, e.g., 1,4-addition and [3 + 2] cycloaddition of 3-tetrasubstituted oxindoles with a calcium Pybox catalyst [11][12], or through enantioselective Friedel–Crafts and carbonyl–ene reactions [13]. Since the pioneering

• set out to elucidate it by using DFT computations (Figure 2). As we have chosen as substrate in our experiments a self-prepared mixture of E- and Z-isomers (9:1) of N-acyl hydrazone 1, which allows for additional binding to oxophilic calcium via the carbonyl oxygen, we did not know a priori which of

• [1,2]H shift is orbital symmetry forbidden and has, hence, a high barrier of 39.8 kcal·mol−1, and also because a – conceivable – intermittently at carbonyl oxygen protonated species (i.e., on an iminol-type pathway) is considerably higher in energy than 10 or 11. The TMS-bound product 12, proposed in

Acyclic cucurbit[n]uril bearing alkyl sulfate ionic groups

• Christian Akakpo,
• Peter Y. Zavalij and
• Lyle Isaacs

Beilstein J. Org. Chem. 2025, 21, 717–726, doi:10.3762/bjoc.21.55

• glycoluril quaternary C-atoms. Third, the Me6CHDA guest is not symmetrically oriented with respect to the ureidyl carbonyl portals of C1. Specifically, one of the methonium N-atoms is located inside the cavity of C1 at 1.4476 Å (0.6162 Å) below the mean plane of the ureidyl carbonyl O-atoms whereas the other

• bind within the anisotropic shielding cavity of C1 whereas the ionic groups reside closer to the ureidyl carbonyl portals of C1. Direct and competitive ITC titrations were used to measure the thermodynamic parameters of binding for C1·guest and M1·guest complexes in PBS solution. Overall, we find that

Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

• scaffolds – alkanes – then we will progress to ethers, alcohols, sugars, amines (and their derivatives), carbonyl compounds, peptides, and finally sulfur-containing compounds. By arranging the material in this way, we hope that newcomers to the field might be able to readily envisage ways to apply these

• reduction of the H-bond-donor acidity of the hydroxy group of 58. (See section 6, which focuses on carbonyl compounds, for a further explanation of the predicted conformation of 58.) Finally, two structural variations on the hydroxy group should be mentioned. First, if the hydroxy group is acylated (i.e

• -chair conformations of the oxocarbenium intermediate (Figure 9) [131][132]. Also, in the preferred pucker, the C–F bond is oriented orthogonal to the C=O group, which makes the carbonyl more electrophilic through mixing of the π*C=O orbital with the σ*C–F orbital. These combined effects enhance both the

Asymmetric synthesis of fluorinated derivatives of aromatic and γ-branched amino acids via a chiral Ni(II) complex

• Maurizio Iannuzzi,
• Thomas Hohmann,
• Michael Dyrks,
• Kilian Haoues,
• Katarzyna Salamon-Krokosz and
• Beate Koksch

Beilstein J. Org. Chem. 2025, 21, 659–669, doi:10.3762/bjoc.21.52

• (d, J = 19.1 Hz), 125.98, 124.25, 71.38, 68.54, 63.06, 58.50, 37.65, 34.44 (d, J = 27.1 Hz), 34.08 (d, J = 26.7 Hz), 30.90, 24.12, 14.86 ppm; 19F NMR (565 MHz, CDCl3) δ −73.28 (d, J = 9.0 Hz) ppm. (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl

• ]− calcd for C25H15F7NO4, 526.0894; found, 526.0871. (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,5-bis(trifluoromethyl)phenyl)propanoic acid [bis(trifluoromethyl)phenylalanine, bisTfMePhe] (3): At room temperature, aq HCl (3 M, 21.4 mL, 64.0 mmol, 5.0 equiv) was added to a stirred solution of 7

• , 48.3, 38.12; 19F NMR (565 MHz, CDCl3) δ −63.42 (s): ATR-FTIR (neat): 3305, 3066, 2971, 1681, 1451, 1278, 1119, 983, 734 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C26H19F6NO4, 546.1116; found, 546.1080. (2S,4R)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-5,5,5-trifluoro-4-methylpentanoic acid

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

• 18.2 (Me-5') characteristic of a 6-chloro-3,4-dihydro-2,5-dimethyl-2H-pyran-2-carbonyl moiety [18]. The chemical shift of C-1' (δC 171.7) in compound 2 compared to 6-chloro-3,4-dihydro-2,5-dimethyl-2H-pyran-2-carbonyl chloride (δC 176.8) indicated that the 6-chloro-3,4-dihydro-2,5-dimethyl-2H-pyran-2

• -carbonyl group was linked through an ester bond and the only hydroxy group available for this esterification was the one at C-7. This compound was finally elucidated as massarilactone D 3,4-di-O-methacryloyl-7-O-(6-chloro-3,4-dihydro-2,5-dimethyl-2H-pyran-2-carbonyl). For the formation of compound 2, an

• oxa-Diels–Alder reaction between two methacryloyl chloride molecules could have taken place to yield 6-chloro-3,4-dihydro-2,5-dimethyl-2H-pyran-2-carbonyl chloride as previously described [18] before esterification of the hydroxy group at C-7. Compounds 3 (6% yield) and 4 (90% yield) were obtained

Total synthesis of (±)-simonsol C using dearomatization as key reaction under acidic conditions

• Xiao-Yang Bi,
• Xiao-Shuai Yang,
• Shan-Shan Chen,
• Jia-Jun Sui,
• Zhao-Nan Cai,
• Yong-Ming Chuan and
• Hong-Bo Qin

Beilstein J. Org. Chem. 2025, 21, 601–606, doi:10.3762/bjoc.21.47

• -position to the carbonyl group in 18 was achieved by using LDA, followed by the addition of 4-bromobenzyl bromide for alkylation, giving compound 16 with 69% isolated yield. Compound 16 was then reduced to alcohol 19 with 2 equiv LAH at 0 °C. The reaction was completed within 10 minutes and the desired

Sequential two-step, one-pot microwave-assisted Urech synthesis of 5-monosubstituted hydantoins from L-amino acids in water

• Wei-Jin Chang,
• Sook Yee Liew,
• Thomas Kurz and
• Siow-Ping Tan

Beilstein J. Org. Chem. 2025, 21, 596–600, doi:10.3762/bjoc.21.46

• antibacterial [1], antiviral [2], anticancer [3], anti-inflammatory [4], and anticonvulsant [5]. Hydantoins were traditionally accessed from amino acids by conversion to urea derivatives followed by cyclization (Urech reaction) or from carbonyl compounds through the cyanohydrin intermediate (Bucherer–Bergs) [6