Dicarboxylate recognition based on ultracycle hosts through cooperative hydrogen bonding and anion–π interactions

• Wen-Hui Mi,
• Teng-Yu Huang,
• Xu-Dong Wang,
• Yu-Fei Ao,
• Qi-Qiang Wang and
• De-Xian Wang

Beilstein J. Org. Chem. 2025, 21, 884–889, doi:10.3762/bjoc.21.72

• obtained using either 1:1 or 1:2 binding models. This is likely due to their intermediate size of chain lengths, which are neither long enough for 1:1 binding nor capable of squeezing a dimer for 1:2 complexation. Notably, the unsubstituted ultracycle B4 [31] without the pendant OH groups on the lower rim

Cu–Bpin-mediated dimerization of 4,4-dichloro-2-butenoic acid derivatives enables the synthesis of densely functionalized cyclopropanes

• Patricia Gómez-Roibás,
• Andrea Chaves-Pouso and
• Martín Fañanás-Mastral

Beilstein J. Org. Chem. 2025, 21, 877–883, doi:10.3762/bjoc.21.71

• reaction in the presence of MeOH in order to trap the potential copper intermediate by protonation. When 2 equiv of MeOH were used, we still obtained the dimerization product 2. Nevertheless, when a catalytic amount of base was used, we only observed the formation of β-borylation product 12 (Scheme 3b

• species A which is in equilibrium with the Cu–O enolate B [11]. In the presence of excess of LiOt-Bu, a salt metathesis reaction between this base and intermediate B generates lithium enolate C and LCuOt-Bu to close the copper catalytic cycle. The formation of a lithium enolate is consistent with the

• . Finally, the new enolate E evolves through intramolecular proton abstraction and elimination of boryllithium [20][21]. The formation of side product 3 observed when dichloromethane was used as a solvent could be explained by protonation of intermediate A, followed by transmetalation of the resulting

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

• ). Pioneering studies have leveraged this platform with great effect, typically invoking π→π* transitions of conjugated alkenes to lower the bond order and generate a triplet diradical, primed for further reactivity. This key intermediate is pivotal in a plenum of synthetic transformations including geometric

• differences in stereoelectronic stabilization of the transient 1,4-biradical intermediate on changing substituent (CO2R→BPin) [63][64][65]. It is pertinent to note that increased catalyst loading and reaction times were necessary for efficient reactivity with alkenylboronic esters, suggesting acrylates are

Chitosan-supported CuI-catalyzed cascade reaction of 2-halobenzoic acids and amidines for the synthesis of quinazolinones

• Xuhong Zhao,
• Weishuang Li,
• Mengli Yang,
• Bojie Li,
• Yaoyao Zhang,
• Lizhen Huang and
• Lei Zhu

Beilstein J. Org. Chem. 2025, 21, 839–844, doi:10.3762/bjoc.21.67

• higher reactivity than 2-bromobenzoic acid derivatives. Based on previously reported literature [7][13], a mechanism for the copper-catalyzed formation of quinazolinones is proposed in Scheme 3. Initially, the 2-halobenzoic acid 1 coordinates with CS@CuI to form intermediate I in the presence of Na2CO3

• , which acts as a base. Subsequently, I undergoes oxidative addition and complexation with the amidine 2 to generate intermediate II. This intermediate then undergoes reductive elimination to form intermediate III, releasing CS@CuI back into the system. Finally, the coupling reaction between the carboxyl

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

• . First, a diazotization of a given aniline 1 and reaction with 2,4-pentanedione gave intermediate 2, with yields which strongly depended on the residue in the para-position. Specifically, the residues bearing an electron-donating group (EDG) such as -OMe or -OH showed low yields because of the poor

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

• log (mL/min/kg) exceeds 0.7, intermediate when that value ranges from 0.3 to 0.7, and low when it is below 0.3 [33]. The total clearance of the studied compounds was observed to range from −0.077 to 0.322 mL/min/kg, indicating low to moderate clearance rates. Additionally, renal excretion via the

Synthesis and photoinduced switching properties of C₇-heteroatom containing push–pull norbornadiene derivatives

• Daniel Krappmann and
• Andreas Hirsch

Beilstein J. Org. Chem. 2025, 21, 807–816, doi:10.3762/bjoc.21.64

• -NBD2 (Supporting Information File 1), demonstrating the intermediate availability of O-QC2. In a similar manner, the aza analogue N-NBD2 was investigated. The UV–vis experiments (Figure 4) yielded results comparable to those obtained for N-NBD1. Initially, the conversion to N-QC2 is anticipated at

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

• , the hydride addition of DIBAL-H to allene 1a catalyzed by 5 mol % IPrCuCl as the optimal catalyst selectively generated the allylaluminum intermediate 2a with >98% conversion [30]. Subsequent addition of one equivalent of TsCN to 2a in a single vessel at room temperature proceeded regioselectively

• hydride complex A through the reaction of IPrCuCl with DIBAL-H [35]. Copper hydride species A reacts regioselectively with allene 1 to form the allylcopper intermediate B. Subsequent transmetalation between allyl-Cu B and DIBAL-H generates allylaluminum species C and regenerates IPrCuH (A). The final step

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

• (O)(OR)2 is derived from the compound P(OR)3, not from HP(O)(OR)2. Although the exact role of HP(O)(OR)2 remains unclear, it has been established that its presence is essential for the C–H phosphorylation. In this case, a radical cation intermediate was suggested for this conversion. Heteroaromatic

• experiments, a radical process was proposed for this coupling reaction via an Mn(III)–P intermediate (Scheme 9). The method was also applied to scale up to gram-scale synthesis. In 2023, Wu et al. [54] also reported another heteroaromatic C–P coupling of benzothiazole with diarylphosphine oxides by an

• reaction proceeded via anodic indole oxidation, followed by a reaction with trialkyl phosphite to give the corresponding indole phosphonate (Scheme 11). Cyclic voltammetry experiments confirmed that free indole can oxidize at the anode and generate a radical-cation intermediate. Also, no product was

Copper-catalyzed domino cyclization of anilines and cyclobutanone oxime: a scalable and versatile route to spirotetrahydroquinoline derivatives

• Qingqing Jiang,
• Xinyi Lei,
• Pan Gao and
• Yu Yuan

Beilstein J. Org. Chem. 2025, 21, 749–754, doi:10.3762/bjoc.21.58

• , we conducted a 5.0 mmol scale reaction and obtained the target product 3aa in 82% yield (Scheme 3). Based on previous reports, a plausible mechanism was proposed. In the presence of a copper catalyst, aniline reacts with cyclobutanone oxime to form an imine intermediate, which undergoes isomerization

• to generate an enamine intermediate. Subsequently, an intermolecular cyclization occurs between the enamine and imine intermediates, ultimately yielding the final target product through an aromatization process (Scheme 4). Conclusion In summary, we have developed an efficient and practical copper

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

• the intermediate exchange regime on the chemical shift timescale for the complexes of C1 with CHDA, Me6CHDA, AdA, Me3AdA (Supporting Information File 1, Figures S10–S13) which is typical of weaker complexes. Third, we observe changes in the chemical shift for the Ha resonance of C1 upon formation of

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

• attached to every carbon of an alkyl chain (e.g., II, Figure 4), then a structure results that is conceptually intermediate between alkanes and perfluoroalkanes. Such structures, dubbed “multivicinal fluoroalkanes”, have interesting conformational properties that are dependent upon the stereochemistry [39

• , most recently, an intermediate twist conformation (31b) [48]. Multiple fluorines can sometimes provide better control. For example, all-syn-1,2,3,4-tetrafluorocyclopentane (33) appears to prefer an envelope conformation with fluorine in the axial position [49]. Another example of conformational control

• ]. Glycosylation reactions (e.g., 63 → 65 and 64 → 66, Figure 9) proceed via an oxocarbenium intermediate. If fluorine is located at C-2, an electrostatic attraction might be expected between the partially negative fluorine and the positively charged C=O+ moiety, and this interaction would favour one of the half

Photochemically assisted synthesis of phenacenes fluorinated at the terminal benzene rings and their electronic spectra

• Yuuki Ishii,
• Minoru Yamaji,
• Fumito Tani,
• Kenta Goto,
• Yoshihiro Kubozono and
• Hideki Okamoto

Beilstein J. Org. Chem. 2025, 21, 670–679, doi:10.3762/bjoc.21.53

• was obtained by a Migita–Kosugi–Stille coupling between bromophenanthrene 15 and (E)-1,2-bis(tributylstannyl)ethene to afford diarylethene 18 followed by Mallory photoreaction. The obtained intermediate 18 contained residual palladium and isolation was not successful due to its poor solubility in

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

• iodides can be efficiently synthesized in gram-scale from the respective fluorinated alcohols using alkyl nonaflates as a key intermediate [13]. Based on these results, 3,3,3-trifluoro-2-methylpropan-1-ol (8) was selected as the starting material. We started our efforts by screening the reaction

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

• the Li/I exchange is essential for preventing racemization of the configurationally labile organolithium intermediate. The subsequent transmetalation with CuBr·P(OEt)3 introduces P(OEt)3 as a supporting ligand, which plays a vital role in stabilizing the resulting chiral organocopper species 14. A key

• electronegativity, reaching 1.648 Å in the reactive alkoxytrialkyl complex D and 1.659 Å in the tetraalkyl "ate" complex E. The B–C bond lengths in amido- and alkyl-substituted boronic ester complexes B and C fell between these extremes, suggesting an intermediate level of activation. These findings prompted

• -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

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

• to give hydantoin H2a with an overall yield of 89%, which indicated complete conversion of the intermediate to the product. Encouraged by the result of the one-pot procedure, we tested the method with amino acids carrying different functional groups on the side chains (Figure 1). Phenol (H2b

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

• conversion of DMSO to MMS, a wide range of 4-arylquinolines can be synthesized (Scheme 8, path I) [24]. In this reaction, the persulfate ion generates the thionium ion (MMS), which is trapped by a nucleophilic aniline. The loss of methyl sulfide generates an imine intermediate B, which, in turn, reacts with

• first reacts with the aniline under cobalt(III) catalysis, and the resulting intermediate C then attacks the thionium ion A. Quinolines of general structure II are formed after the loss of methyl sulfide from intermediate D, followed by final cyclization of intermediate E (Scheme 8, path II

• ). Additionally, the Tiwari group developed a metal-free protocol using only K2S2O8 as an oxidant for the activation of DMSO to MMS (Scheme 8, path II) [38]. Under these conditions, an alternative mechanism arises in which the imine intermediate B, formed as previously stated through reaction between the aniline

Study of the interaction of 2H-furo[3,2-b]pyran-2-ones with nitrogen-containing nucleophiles

• Constantine V. Milyutin,
• Andrey N. Komogortsev and
• Boris V. Lichitsky

Beilstein J. Org. Chem. 2025, 21, 556–563, doi:10.3762/bjoc.21.44

• isolation of intermediate salt 3a. Indeed, the reflux of starting compound 1a with amine 2a in AcOH for 24 h led to formation of product 4a with 62% yield. Using various furanones 1 and amines we attempted to synthesize analogues of compound 4a based on the above procedure. It was found that the presence of

• fragment leads to hemiaminal A. Then, enamine 4 is formed via dehydration of intermediate B. In the case of amines 2 the reaction stops at this stage while for other substrates the further recyclization proceeds. So, the additional NH or OH fragment attacks the lactone moiety leading to intermediate C. The

Asymmetric synthesis of β-amino cyanoesters with contiguous tetrasubstituted carbon centers by halogen-bonding catalysis with chiral halonium salt

• Yasushi Yoshida,
• Maho Aono,
• Takashi Mino and
• Masami Sakamoto

Beilstein J. Org. Chem. 2025, 21, 547–555, doi:10.3762/bjoc.21.43

• present reaction, and products 17l and 17m were isolated in high yields with moderate to high stereoselectivities. The plausible reaction mechanism is shown in Figure 3. First, the removal of the acidic proton of the pre-nucleophile by potassium carbonate to form intermediate I, which undergoes cation

• exchange from tetrafluoroborate to the halonium moiety to form chiral ion pair II. Attack of the chiral nucleophilic intermediate II to imine 7 leads to intermediate III. The latter is protonated by in the situ-formed potassium bicarbonate to form the desired product 17, together with the regenerated

Vinylogous functionalization of 4-alkylidene-5-aminopyrazoles with methyl trifluoropyruvates

• Judit Hostalet-Romero,
• Laura Carceller-Ferrer,
• Gonzalo Blay,
• Amparo Sanz-Marco,
• José R. Pedro and
• Carlos Vila

Beilstein J. Org. Chem. 2025, 21, 533–540, doi:10.3762/bjoc.21.41

• the double bond to the carbonyl in a relative re-si approach, generating intermediate I, which undergoes a tautomerization to recover the aromatic pyrazole ring. The increased yield observed in some cases with SQ-1 may be attributed to the formation of additional hydrogen bonds that enhance

Synthesis of electrophile-tethered preQ₁ analogs for covalent attachment to preQ₁ RNA

• Laurin Flemmich and
• Ronald Micura

Beilstein J. Org. Chem. 2025, 21, 483–489, doi:10.3762/bjoc.21.35

• was observed, and the alcohol intermediate was isolated in pure form. In both cases, quantitative bromination was achieved by heating the compounds in concentrated aqueous hydrobromic acid, which after evaporation afforded the pure compounds 4b–d. To generate iodide 4e, alcohol 11 was isolated and

• 3b in almost quantitative yield. The bis(3-bromopropyl)-modified ligand 3c was generated by heating preQ1 together with bis(3-hydroxypropyl)amine. It is noteworthy that the amine exchange reaction is thought to proceed via a purine methide intermediate [11]. Subsequent treatment of the diol with

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

• 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

• entry 2 versus entry 6 in Table 2). Furthermore, we studied the effect of using an organic acid as the co-catalyst for forming the enamine intermediate from 1 and for the retro-Michael reaction. We observed that benzoic acid (BA) as a co-catalyst provides a lower er than that achieved with PNBA as a co

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

• approach would conceptually differ from previously reported anodic syntheses of cyclic diaryl iodonium compounds, where an electrochemically generated acyclic iodine(III) intermediate undergoes an intramolecular SEAr-type reaction to form the cyclic product [19][20]. Herein, we report on the development of

• moiety would help to stabilize the key λ3-bromane(III) intermediate 5, as demonstrated in the work of Miyamoto et al. [21], thus facilitating its formation in anodic oxidation. The anodic oxidation of 4a under previously published conditions for the synthesis of Br(III) species [16][18] (GC as working

• starts with a single-electron oxidation of 4a on the electrode surface to form cation radical A, in which Br(II) is chelation-stabilized by the carboxyl group [21] and the neighbouring Br substituent [24]. Intermediate A rapidly undergoes irreversible chemical reaction by HFIP coordination to transient

Identification and removal of a cryptic impurity in pomalidomide-PEG based PROTAC

• Bingnan Wang,
• Yong Lu and
• Chuo Chen

Beilstein J. Org. Chem. 2025, 21, 407–411, doi:10.3762/bjoc.21.28

• also be explained by C4 being located near the node of the LUMO. However, SNAr is still favored over glutarimide displacement potentially because the negative charge in the corresponding intermediate is stabilized by an extended conjugation system. In contrast, the negative charge in the carbonyl

• addition intermediate is stabilized by an oxygen atom only. As such, the erosion of 3 by taurine was minimal. Conclusion Nucleophilic aromatic substitution of 4-fluorothalidomide (1) has provided a convenient entry to the IMiD class of PROTAC molecules. Although the yield of the desired product 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

• directions away from the central oxocarbenium ion intermediate in the limiting dissociative process involving diastereomeric ion pairs. Destabilisation and greater reactivity of the oxocarbenium intermediate causes the nucleophilic acceptor moiety to attack in a concerted process following a classical SN2

• evidence of the associative end of the mechanistic spectrum has been shown and supported by Crich et al. [36]. The group has also reported instances wherein the triflate counterion may also act as a strong nucleophile [37] to form a loosely bound covalent glycosyl triflate intermediate further leading to

• in attaining the required stereospecific glycosylation outputs. Apart from the widely convenient stepwise synthesis, recently one-pot glycosylations have also made an important mark which minimise the tedious purification of the intermediate molecules in each step [53][54][55][56][57][58]. In the