Synthetic approach to borrelidin fragments: focus on key intermediates

• Yudhi Dwi Kurniawan,
• Zetryana Puteri Tachrim,
• Teni Ernawati,
• Faris Hermawan,
• Ima Nurasiyah and
• Muhammad Alfin Sulmantara

Beilstein J. Org. Chem. 2025, 21, 1135–1160, doi:10.3762/bjoc.21.91

• to afford the corresponding sulfone 41. However, Uguen found that a more efficient route involved treating alcohol 40 with tosyl chloride in pyridine and DMAP, followed by nucleophilic displacement with sodium thiophenol and oxidation of the resulting sulfide with m-CPBA, yielding sulfone 41 in 85

• iodide, and subsequent nucleophilic substitution with deprotonated (R,R)-91. The introduction of the OPMB functionality in compound 88 could then be achieved by following the steps employed in the transformation of 84 to 83. The synthesis via route A began with efforts to optimize the epimerization of

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

• vitro and in vivo antimalarial drug leads. With a view to generating a library of unique antimalarial 1,2,4-triazolo[4,3-a]pyrazines and exploring regiochemical preference for nucleophilic amines, we utilised the known synthetic 5-chloro-3-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyrazine (1) as a

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

• initiate the disassembly of the HIM trimer into a HIM monomer [18]. The HIMs were found not to interact with tetrabutylammonium nitrate, signifying a lack of association between the HIM and the bulky cation (tetrabutylammonium) or the non-nucleophilic anion (nitrate). With these observations, and the

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

• with nucleophilic cinnamonitrile 149 to give benzocyclooctene 150 via iodonium intermediate 151 (Scheme 46) [86]. 2.2 Oxidative acylations Cinnamic ester or amide preparation could also be achieved by oxidizing cinnamyl alcohol, aldehyde, imine, and ketone as an alternative to the traditional O/N

• catalytic Wittig reaction using phosphetane oxide 412 as redox cycling catalyst using silanes as the reductant to convert aldehydes and α-bromoesters into the corresponding cinnamate esters 44, 154, and 413. The reaction proceeds via formation of nucleophilic phosphane 414 (Scheme 87A) [147]. Moreover

Pd-Catalyzed asymmetric allylic amination with isatin using a P,olefin-type chiral ligand with C–N bond axial chirality

• Natsume Akimoto,
• Kaho Takaya,
• Yoshio Kasashima,
• Kohei Watanabe,
• Yasushi Yoshida and
• Takashi Mino

Beilstein J. Org. Chem. 2025, 21, 1018–1023, doi:10.3762/bjoc.21.83

• reaction with nucleophilic lithium amide from n-propylamine, the reduction of phosphine oxide 9 by trichlorosilane/triethylamine, and the N-acylation of 10 with cinnamoyl chloride in three steps (Scheme 1). We also analyzed amide compound 7 by HPLC analysis using a chiral stationary phase column with a CD

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

• incorporated into cyclization reactions. The iminium species generated from enamides via nucleophilic addition or substitution are capable of engaging in further electrophilic additions or isomerization processes. Exploiting the multiple reactivities of enamides facilitates the development of diverse

• particular emphasis on their pivotal role as a strategy in the total synthesis of natural products. Keywords: alkaloid; cyclization; enamide; natural product; total synthesis; Introduction The use of enamines as surrogates for enols in nucleophilic reactions has been well-documented for decades since their

• nucleophilic addition or substitution, the resulting iminium ions often undergo direct hydrolysis, preventing further use in a cascade nucleophilic addition. As a result, enamines are not ideal partners in tandem reactions for the synthesis of nitrogen-containing products. As analogues to enamines, the

On the photoluminescence in triarylmethyl-centered mono-, di-, and multiradicals

• Daniel Straub,
• Markus Gross,
• Mona E. Arnold,
• Julia Zolg and
• Alexander J. C. Kuehne

Beilstein J. Org. Chem. 2025, 21, 964–998, doi:10.3762/bjoc.21.80

• functionalization with a much broader variety of donors (and even acceptors) than is possible through a radical-mediated nucleophilic aromatic substitution (SRN1, see also below) [3][46][47]. The I-TTM has a maximum emission at λem = 578 nm and a ϕ of 3% (in cyclohexane), indicating that the symmetry does not seem

• precise C–C and C–N cross-coupling reactions only at the site of the iodine – donors were attached to TTM by radical-mediated nucleophilic aromatic substitution SRN1. The leaving group is the para-chlorine atom, of which a TTM molecule has three. It is therefore less than surprising that during this SRN1

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

• heteroannulation leading to the pyrazolo[1,5-a][1,4]diazepine scaffold. Our initial choice was to investigate the use of silver(I) triflate (AgOTf) as a catalyst in toluene, given its previously demonstrated efficiency in various transformations involving the activation of triple bonds towards nucleophilic attack

• 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

• atom prevents the reaction by blocking the nucleophilic attack on the triple bond or the subsequent proton transfer step, thereby preventing substrates 15y and 15z from undergoing the described heteroannulation. Additionally, the alternative carbocyclization pathway cannot occur, as the vacant 4C

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

• enhanced electrophilicity of palladium facilitates preferential coordination with the amino group and activates the alkyne to form the intermediate Int-14 instead of Int-14'. Subsequent nucleophilic cyclization generates intermediate Int-15. Following CO insertion, complex Int-16 is formed, and reductive

• the hydroxy group to form complex Int-17 and the amino group undergoes nucleophilic attack to generate Int-18. After CO insertion complex Int-19 is produced and reductive elimination ultimately affords the indolo[3,2-c]coumarin product 10. In 2023, the Garg group achieved the first example of

• environment around the copper center disfavors a direct interaction with nucleophilic alkyl radicals. Instead, the reaction proceeds via an outer-sphere mechanism, where the alkyl radical reacts with the copper-activated C=N unsaturated bond, enabling stereocontrolled C(sp3)–C(sp3) coupling. In contrast, with

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

• ). Therefore, excess methylamine (40% in water, 47 equiv), served as both the solvent and nucleophilic reactant in the above reaction. In the 1H NMR spectrum of 3a, there are two doublets of doublets at 4.40 ppm and 4.49 ppm corresponding to two methylene protons (CH2) which are diastereotopic and therefore

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

• -catalyzed regioselective hydroalumination of allenes using diisobutylaluminum hydride (DIBAL-H), we envisioned that the nucleophilic attack of allylaluminum reagents on electrophilic cyanating reagents could provide a regioselective pathway for the synthesis of alkyl nitriles bearing quaternary carbon

• involves the regioselective nucleophilic attack of allylaluminum C on tosyl cyanide, which proceeds at the γ-position via six-membered ring transition state D, leading to the formation of the desired nitrile product. Transition state D is responsible for the E-selectivity observed in trisubstituted allenes

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

• )(OR)2. The final product was formed by a simple nucleophilic substitution of the phosphorus center (Scheme 20). The N–P bond formation is a critical process in organic synthesis due to the preparation of various materials with different biological and medicinal activities. In 2021 Wang et al. [65

• reaction proceeded with anodic oxidation of iodide to iodine, followed by a reaction with dialkyl phosphite to give I–P(O)(OR)2. The final product was formed by a simple nucleophilic substitution of phenols with I–P(O)(OR)2. In 2021, Wang et al. [65] presented a report on electrochemical P–O bond formation

• the rings contained electron-withdrawing groups. It is suggested that the reaction proceeded via single-electron oxidation of thiocyanate at the anode. DBU was used in the reaction for a simple nucleophilic substitution of phosphonate with a cyanide group in the formed intermediate (Scheme 28). In

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

• observation of enantioselectivity must be explained by relative energies of stereoisomeric forms of TS 9-10. Reversible formation of product 10 from nucleophilic addition step via TS 9-10 is slightly endothermic (Figure 3). In 10, cyanide is still attached via nitrogen to calcium, forming a formal Ca–N–C–C–N

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

• conditions were optimized for the effective formation of tetrahydroquinoline derivatives with varying substituents, showing high yields under mild conditions. Mechanistic studies suggest a catalytic cycle involving nucleophilic attack by the aniline on the cyclobutanone oxime, followed by cyclization to form

• into tetrahydroquinoline (THQ)-based 6-6-4-membered ring systems through a combination of nucleophilic addition and borate-mediated [2 + 2] photocycloaddition, offering a catalyst-free approach to construct conformationally constrained 2D/3D frameworks with high functional group compatibility and

Orthogonal photoswitching of heterobivalent azobenzene glycoclusters: the effect of glycoligand orientation in bacterial adhesion

• Leon M. Friedrich and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2025, 21, 736–748, doi:10.3762/bjoc.21.57

• azobenzene derivative 9 [34] to furnish 10. This reaction had to be carried out at −78 °C in order to suppress nucleophilic substitution of the ortho-fluorine substituents in 9 by the thiol 8, a reaction that competes with the desired cross-coupling. For the second Buchwald–Hartwig–Migita cross-coupling, the

Synthesis of HBC fluorophores with an electrophilic handle for covalent attachment to Pepper RNA

• Raphael Bereiter and
• Ronald Micura

Beilstein J. Org. Chem. 2025, 21, 727–735, doi:10.3762/bjoc.21.56

• nucleophilic aromatic substitution of 4-fluorobenzaldehyde with 2-(methylamino)ethanol, 3-methylamino-1-propanol or 2-[2-(methylamino)ethoxy]ethan-1-ol in the presence of potassium carbonate to afford benzaldehyde derivatives 1, 2, and 3 in excellent yields. Next, the piperidine-induced condensation with 4

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

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

• largely depends on the choice of the nucleophilic organometallic species (Scheme 2). For example, the asymmetric copper-catalyzed allylic alkylation utilizing organometallic species 5 bearing a primary carbon–metal bond predominantly constructs the stereogenic center derived from electrophiles. The

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

• conversion of the thioether-containing methionine to hydantoin (H2j) was obtained with a moderate yield of 59%. Lastly, no hydantoin product was observed by 1H NMR when cysteine was subject to the one-pot procedure, possibly due to disulfide formation of the highly nucleophilic thiol group of the cysteine

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

• decompose into DMS (dimethyl sulfide), which then can act as a nucleophile in several MCRs (Scheme 4) [19][20][21][22]. In this context, DMSO can be used as a source of the methylsulfanyl (-SCH3) group after DMS follows a nucleophilic addition or substitution, allowing one to obtain different types of

• nucleophilic species present in the reaction medium, MMS can act as a methylene source. Under hydrolysis conditions, it can be a source of formaldehyde (Scheme 5a), but with other nucleophiles, after nucleophilic addition, the sulfide group can work as a leaving group, allowing for a sequential domino process

• 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

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

• subsequent opening of the furanone ring and proton transfer results in final compounds 8, 10 and 11. The synthetic application of obtained pyrazolones 8 was demonstrated by its further derivatization. The interaction with electrophilic agents is determined by the presence of several nucleophilic centers in

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

• 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

• diastereoselectivity (up to 7:1). Keywords: alcohols; diastereoselectivity; nitrogen heterocycles; pyrazoles; vinylogous reaction; Introduction Vinylogy refers to the transmission of electronic effects through a conjugated π-system, enabling the extension of a functional group's nucleophilic or electrophilic

• biologically active compounds, particularly antibacterial and antifungal agents [13][14]. This class of functionalized nitrogen heterocycles is notable for its synthetic versatility, because it shows different nucleophilic positions, making regioselectivity a synthetic challenge. Numerous studies have reported

• functionalize 5-aminopyrazoles. Biologically active compounds featuring a trifluoromethyl carbinol motif. Nucleophilic sites of 5-aminopyrazoles and 4-alkenyl-5-aminopyrazoles. Stereoselective synthesis of trifluoromethyl carbinols through an vinylogous addition reaction of 4-alkenyl-5-aminopyrazoles to alkyl

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

• phosphodiesters by 105–107 by electrophilic activation of ester and nucleophilic activation of water or peroxide at the metal ion [101][102]. The takeaway message is that polarization is most effective when it is bifunctional. In enzymes, there is never just a nucleophile – there is always a metal, “oxyanion hole

• generated large electrostatic effects by functionalizing the capsule exteriors with charged groups (Figure 4D) [136][137]. Observed rate accelerations for capsule-promoted nucleophilic substitution reactions demonstrate significant enthalpic stabilization of the transition state attributable due to the

• nucleophile and electrophile in a glycosylation reaction [105]. (D) An externally charged cavitand promotes charge-stabilized nucleophilic substitution reactions of hydrophobically encapsulated substrates [136][137]. (A) Metal-organic cages and key modes in catalysis. (B) Charged metals or ligands can result

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

• drug”) class of PROTAC molecules with a PEG linker is frequently used to promote targeted protein degradation. The standard protocol for their synthesis involves nucleophilic aromatic substitution of 4-fluorothalidomide with a PEG-amine. We report herein the identification of a commonly ignored

• impurity generated in this process. Nucleophilic acyl substitution competes with aromatic substitution to displace glutarimide and gives a byproduct that can co-elute with the desired product on HPLC throughout the remainder of the synthesis. Scavenging with taurine is a convenient way to minimize this

• contamination. Keywords: glutarimide; IMiD; impurity; nucleophilic acyl substitution; PROTAC; Introduction Targeted protein degradation capitalizing on the concept of chemically induced dimerization has emerged as a new therapeutic approach recently [1]. In particular, the modularity of proteolysis targeting