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

• and the resulting 1,3-acetyloxyiodides 37 were treated in situ with methanolic t-BuOK to promote the cyclisation. Best results for the oxetane formation were obtained for dimethylphenylvinylsilane, while alkenes without the silyl group afforded mainly homoallylic alcohols 39, presumably through an

• groups including esters, ketones, sulphones and heteroaryls. The mechanistic proposal, supported by DFT calculations, starts with an oxidative decarboxylation to give an aminooxetanyl radical 157. This species is in turn coupled with the aryl halide by the active Ni(0) catalyst (generated in situ by

• followed by an acid-catalysed intramolecular oxetane opening (Scheme 53) [107]. Although it is not a true domino process as the ring opening does not take place in situ, the work-up after the first step involves only a short column

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

Optimized synthesis of aroyl-S,N-ketene acetals by omission of solubilizing alcohol cosolvents

• Julius Krenzer and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2025, 21, 1201–1206, doi:10.3762/bjoc.21.97

• 1 suggests starting from aroyl chlorides 2 and 2-methyl-N-benzylbenzothiazolium salts 3 by a condensation transform (Scheme 1). The condensation essentially represents an addition–elimination sequence that starts with the nucleophilic S,N-ketene acetal 4, in situ generated from substrate 3 by

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

• situ formation of an active enol ester 26. The phenol was formed in situ during the second step from phenylboronic acid oxidation utilizing H2O2 (30%) as green oxidant (Scheme 8B) [40]. Sureshbabu and co-workers (2023) activated the carboxyl group of 4-hydroxycinnamic acid (1) by selectively reacting

• in situ nitro reduction using Mn powder to afford the amide intermediate 42. The acid halide once again was applied for cinnamic acid amidation. Xiao and co-workers (2021) performed a transesterification and aminolysis of the tert-butyl ester 43 simply by using PCl3 through in situ generation of the

• pentafluoropyridine (PFP) via in situ formation of an active acid fluoride 48 to afford the corresponding amides 13 and 47 in moderate yields (Scheme 15) [47]. In addition, the amidation process could be scaled up to a gram scale to give 47 in 90% yield. Maruoka and co-workers (2021) converted cinnamic esters into

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

• inconsequential due to the reversibility of hemiaminal. Consequently, further reduction of the amide could complete the total synthesis of (+)-fawcettimine with in situ adjustment of the hemiaminal configuration. The incorrect configuration observed in the Mukaiyama hydration also inspired the authors to develop

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

• carbon monoxide were used as starting materials, and two natural product frameworks of phenanthridone and acridone alkaloids could be selectively obtained by controlling ligands. The reaction of o-iodoaniline with in situ-generated arynes under CO atmosphere under ligand-free conditions selectively

• utilizing in situ-generated π-allylpalladium complexes to capture strained cyclic allene intermediates (Scheme 4) [22]. By modulating the ligands in the reaction system, two distinct polycyclic scaffolds, 13 or 14, could be synthesized with high selectivity. Mechanistically, the Pd(0) catalyst coordinates

• formation of intermediate Int-87 via oxidative addition. Rapid coupling with the in situ-generated acyl radical produces copper-bound intermediate Int-88. Base-mediated anionic exchange then displaces the halide ligand with amine, yielding intermediate Int-89. Final reductive elimination from this species

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

• . Access to vicinal boron scaffolds 4f and 4g provided conclusive evidence that sensitization of alkenylboronic esters is achievable using xanthone, with in situ oxidation enabling direct access to otherwise challenging to synthesize cyclobutyldiols. The lower observed diastereoselectivity may reflect

Regioselective formal hydrocyanation of allenes: synthesis of β,γ-unsaturated nitriles with α-all-carbon quaternary centers

• Seeun Lim,
• Teresa Kim and
• Yunmi Lee

Beilstein J. Org. Chem. 2025, 21, 800–806, doi:10.3762/bjoc.21.63

• for the in situ generation of hydrogen cyanide (Scheme 1a). This method achieved high regioselectivity and enantioselectivity, highlighting the potential of allene hydrocyanation for the synthesis of complex nitrile-containing products. In another approach, the Minakata group used electrophilic

• scope for the formal hydrocyanation with 1,1-disubstituted and 1,1,3-trisubstituted allenes was examined (Scheme 3). All reactions were performed in the presence of 5 mol % IPrCuCl to generate the allylaluminum reagents in situ, followed by cyanation at room temperature for 30 min. This method

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

• reaction proceeded via an oxidative addition and reductive elimination processed in the presence of Ni(0), which was produced in situ from NiBr2 in the cathode. Palladium is one of the most important metals used as a catalyst in non-electrochemical reactions. In 2020, Budnikova et al. [58] reported a

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

• , depending on the catalyst loading. This result underscores the importance of calcium in complex 4 for this particular transformation. We assume that the conversion of complex 4 to the active catalytic species might rely on the in situ formation of the cyanide species from the reaction between Ca complex 4

• our previous work [45], we carried out the enantioselective hydrocyanation of hydrazones using Ca–BINOL phosphate complex 6 at −10 °C in DCM for 72 h. In addition to those reaction conditions, we initially used t-BuOH as an additive [45]. The Ca–BINOL phosphate complex 6 was prepared in situ by

• hydrocyanation product with opposite chirality was obtained, in comparison to experiments with the in situ formed Ca complex (Table 2, entries 1–3). It appears that the way in which catalyst 6 is generated (pre-formed or in situ), has a major influence on enantioselectivity, while the addition of t-BuOH has

Recent advances in allylation of chiral secondary alkylcopper species

• Minjae Kim,
• Gwanggyun Kim,
• Doyoon Kim,
• Jun Hee Lee and
• Seung Hwan Cho

Beilstein J. Org. Chem. 2025, 21, 639–658, doi:10.3762/bjoc.21.51

• reversed by adding zinc halides (Scheme 4). When treated with allylic phosphates 17 in the presence of ZnCl₂, these copper reagents 14 showed a dramatic shift in selectivity, favoring SN2' substitution. This exceptional reversed regioselectivity likely occurs through the in situ formation of copper–zinc

• consistent stereochemical outcome highlight its practical utility. Their subsequent work with chiral tertiary boronic esters 25 revealed an effective strategy for constructing quaternary stereogenic centers through allylic substitution reactions (Scheme 8) [48]. By employing in situ-generated

• -trifluoromethylalkenes 38 with hydrosilanes and allylic chlorides 40 (Scheme 14b) [55]. In their work, a chiral α-CF3 alkylcopper intermediate 39 was formed through the regio- and enantioselective hydrocupration of electron-deficient alkenes 38 with an in situ-generated CuH species. Subsequent electrophilic trapping of

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

• 14 was performed next and the desired iodide was isolated and, to our delight, the cleavage of the MOM group occurred concomitantly, affording compound 15 in 75% yield. This reaction is likely triggered by the in situ-generated acid. As in our previously reported synthesis, a Zn/AcOH reductive

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

• reactions [10]. Oxidation of the alcohol is done in situ to avoid problems regarding the isolation and instability of the aldehyde produced, although undesirable reactions, such as oxidation of the amines or isocyanides or overoxidation of the alcohol, could also be problematic [11][12]. In this regard

• the alkene moiety of the amine. The resulting stabilized carbocation 15 is then captured by formaldehyde (generated in situ from DMSO) leading to an intermediate oxocarbenium 16 that undergoes a cyclization to obtain the sulfenylated oxazinane derivative 13. In isotope labelling experiments using DMSO

• -d6 the expected deuterated product 17 is obtained, confirming the in situ generation of formaldehyde from DMSO as the source of the methylene group. Interestingly, the reaction gives better yields under these conditions than that observed when paraformaldehyde is used. DMSO in Mannich-type MCRs Sun

Photomechanochemistry: harnessing mechanical forces to enhance photochemical reactions

• Francesco Mele,
• Ana M. Constantin,
• Andrea Porcheddu,
• Raimondo Maggi,
• Giovanni Maestri,
• Nicola Della Ca’ and
• Luca Capaldo

Beilstein J. Org. Chem. 2025, 21, 458–472, doi:10.3762/bjoc.21.33

• ). Overall, it was concluded that 7.1 and 7.2 first react to give 7.4 via a dark mechanochemical thiol–yne reaction; the latter is then converted to 7.3 by singlet oxygen generated in situ, by eosin Y. It is important to notice here that the reaction is proposed to proceed according to a different

• technique for high-throughput experimentation [83]. A further area of development would be the possibility of integrating options for the in-situ monitoring of reactions, such as X-ray and Raman techniques [47][48][84][85][86][87]. In conclusion, in recognizing that both photochemistry and mechanochemistry

Electrochemical synthesis of cyclic biaryl λ³-bromanes from 2,2’-dibromobiphenyls

• Andrejs Savkins and
• Igors Sokolovs

Beilstein J. Org. Chem. 2025, 21, 451–457, doi:10.3762/bjoc.21.32

• diaryl λ3-bromanes under remarkably mild conditions with subsequent applications of the in situ-generated arynes in cycloaddition reactions [3], meta-selective reactions with oxygen and nitrogen nucleophiles [4][5], regiodivergent meta or ortho-alkynylations [6], and regioselective (di)halogenation [7

• molecular nitrogen in diazonium compounds. Accordingly, pre-formed [12] or in situ-generated 2,2’-bromodiazonium salts 2 [11][13][14] furnish cyclic bromine(III) species 1 under thermal decomposition conditions (Scheme 1, reaction 1). The diazonium intermediates 2 are obtained by diazotation of 2'-bromo

Beyond symmetric self-assembly and effective molarity: unlocking functional enzyme mimics with robust organic cages

• Keith G. Andrews

Beilstein J. Org. Chem. 2025, 21, 421–443, doi:10.3762/bjoc.21.30

• able to adapt this chemistry to work in situ, allowing soluble metastable imine frameworks to be trapped as amides [38]. The adapted cages were soluble, and were now stable enough to be purified by gel-permeation (size-exclusion) chromatography (useful when precipitation is not possible), which is

The effect of neighbouring group participation and possible long range remote group participation in O-glycosylation

• Rituparna Das and
• Balaram Mukhopadhyay

Beilstein J. Org. Chem. 2025, 21, 369–406, doi:10.3762/bjoc.21.27

• stoichiometric amount of sodium methoxide [88] generated in situ where the authors postulated an associative SN2 pathway as they were unable to isolate any bicyclic orthoester intermediate from the crude mixture. With the aim to get similar neighbouring group protection at C-2 position, it was observed that the

Synthesis, structure, ionochromic and cytotoxic properties of new 2-(indolin-2-yl)-1,3-tropolones

• Yurii A. Sayapin,
• Eugeny A. Gusakov,
• Inna O. Tupaeva,
• Alexander D. Dubonosov,
• Igor V. Dorogan,
• Valery V. Tkachev,
• Anna S. Goncharova,
• Gennady V. Shilov,
• Natalia S. Kuznetsova,
• Svetlana Y. Filippova,
• Tatyana A. Krasnikova,
• Yanis A. Boumber,
• Alexey Y. Maksimov,
• Sergey M. Aldoshin and
• Vladimir I. Minkin

Beilstein J. Org. Chem. 2025, 21, 358–368, doi:10.3762/bjoc.21.26

• sensitivity of in situ obtained complexes 9 and 10 with CN− to different cations. It appeared that the addition of an equivalent amount of Hg(ClO4)2 to an acetonitrile solution selectively and completely restores the initial absorption and fluorescence spectra (Scheme 3). Thus, the obtained compounds

Oxidation of [3]naphthylenes to cations and dications converts local paratropicity into global diatropicity

• Abel Cárdenas,
• Zexin Jin,
• Yong Ni,
• Jishan Wu,
• Yan Xia,
• Francisco Javier Ramírez and
• Juan Casado

Beilstein J. Org. Chem. 2025, 21, 277–285, doi:10.3762/bjoc.21.20

• conducted on a Cary 5000 spectrophotometer. A C3 epsilon potentiostat from BASi was used for the electrolysis using a thin layer cell from a demountable Specac® Omni cell. In this cell, a three-electrode system was coupled to conduct in situ spectroelectrochemistry. A Pt gauze and a Pt wire were used as

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

• role in most cases is to generate highly reactive species in situ from the nucleophilic reaction component. This can subsequently interact with other reaction components to form target products. Compared to the crotonic condensation products of other aliphatic and aromatic aldehydes, methylidene

Streamlined modular synthesis of saframycin substructure via copper-catalyzed three-component assembly and gold-promoted 6-endo cyclization

• Asahi Kanno,
• Ryo Tanifuji,
• Satoshi Yoshida,
• Sota Sato,
• Saori Maki-Yonekura,
• Kiyofumi Takaba,
• Jungmin Kang,
• Kensuke Tono,
• Koji Yonekura and
• Hiroki Oguri

Beilstein J. Org. Chem. 2025, 21, 226–233, doi:10.3762/bjoc.21.14

• reaction involves an in situ generation of the iminium cation A followed by isomerization to the thermodynamically more stable iminium cation B. Subsequent nucleophilic attack of a copper acetylide enabled regioselective C–C bond formation at the C11 position. After removal of the cyclic acetal, the

• isoquinoline ring via gold(I)-mediated 6-endo hydroamination (Scheme 2). Treatment of 11 with a cationic gold complex, generated in situ from AuCl(PPh3) and AgNTf2 [47][48][49][56], with an excess amount of triethylamine in 1,2-dichloroethane at 65 °C, resulted in the intended regiocontrolled hydroamination

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

• esters containing a quaternary stereocenter, and the control of regioselectivity depended on the bulkiness of the substrates. Additionally, the electrochemical system served as an internal syringe pump, generating quinone from hydroquinone in situ through anodic oxidation, which enhanced the

• performed using electrophilic chlorinating reagents or stable and readily available chloride sources with stoichiometric amounts of chemical oxidants. However, in this catalytic system, chloride (Cl−) from HCl was used as the chlorinating agent, and electrophilic chlorine (Cl+) was generated in situ by the

• enantio-determining transition states. Based on the mechanistic studies, a reaction mechanism is proposed in Figure 14. First, the in situ-generated Cu(I)–CN complex 83 is oxidized at the anode to form a Cu(II)–CN complex 84, which reacts with diarylphosphine oxide 80 to generate a transient P-centered

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

• involves a Friedel–Crafts alkylation of the arene followed by hydroamination (Scheme 6) [5]. The mechanism plausibly starts with the in situ formation of triflic acid from Cu(OTf)2 which leads to protonation of the oxygen atom of the alcohol with generation of the activated allyl alcohol. This latter gives

• ]. Three-component coupling of amines, aldehydes or ketones, and terminal alkynes catalyzed by Cu(OTf)2 is a fruitful tool for the production of α-substituted propargylamines 10 (Scheme 7) [20]. The reaction involves the alkynylation of the corresponding imines formed in situ and provides higher yields

• (Scheme 16) [33]. The reaction, which occurs with formation of C–C, C–N and C–O bonds, involves a nucleophilic addition of the activated alkyne XIV to the in situ-generated iminium ion XV, followed by cyclization to form a quinoxalin-2-one intermediate XVI. A subsequent 5-endo-dig cyclization involving

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

• be carried out in a one-pot fashion with comparable results and without significant variation from the two-step procedure. Utilization of the Povarov reaction and subsequent oxidation by DDQ was also done by Wang et al. in 2020 [54]. In situ-formed imines from anilines 91 and benzaldehydes 92 were

Reactivity of hypervalent iodine(III) reagents bearing a benzylamine with sulfenate salts

• Beatriz Dedeiras,
• Catarina S. Caldeira,
• José C. Cunha,
• Clara S. B. Gomes and
• M. Manuel B. Marques

Beilstein J. Org. Chem. 2024, 20, 3281–3289, doi:10.3762/bjoc.20.272

• reagents (HIRs) bearing a benzylamine with in situ-generated sulfenate salts was investigated. Under the studied conditions sulfonamides have been obtained in up to 52% yield. This reaction has been extended to a variety of HIRs and sulfenate salts to explore the different reactivity of these new reagents

• benziodoxolone was generated in situ, via a reaction of chlorobenziodoxolone with sulfinate salts, followed by the addition of amines or hydrazines, respectively. On the follow-up on our research, we envisaged to extend the diversity of BBX reagents as electrophilic amine reagents and investigated their

• reactivity with in situ-generated sulfenate anions, from β-sulfinyl esters, to achieve S–N bond formation. The importance of establishing this S–N bond results from the widespread presence of sulfonyl-containing bioactive compounds, such as the sulfonamide group which can be found in many pharmaceuticals