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

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

• to a sulfate group. The synthetic route to C1 starts with the double electrophilic aromatic substitution reaction of methylene-bridged glycoluril tetramer (TetBCE) with W1 in TFA/Ac2O 1:1 which adds the sidewalls and transforms the OH groups into OAc groups to give TetW1OAc in 71% yield as described

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

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

• -extension (ΔλABS = ca. 6 nm per increment of one benzene ring) and the spectral profiles resemble each other irrespective of the length of the phenacene π conjugation and the fluorine substitution. The results suggest that these factors could provide insignificant effects on the apparent electronic spectral

• that, through the fluorination, one can tune the MO energy levels without changing the apparent electronic spectral features in solution, such as, electronic spectral shapes, wavelengths, and fluorescence quantum yields. Such fluorine-substitution effects on electronic spectra and MO levels were

• the fluorination. By contrast, in the solid phase, F8PIC, F8FUL, and F87PHEN showed significantly broadened and red-shifted fluorescence bands indicating that the intermolecular interactions in the solid phase were modified by the fluorine substitution. The present results could provide a strategy for

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

• Abstract The transition-metal-catalyzed asymmetric allylic substitution represents a pivotal methodology in organic synthesis, providing remarkable versatility for complex molecule construction. Particularly, the generation and utilization of chiral secondary alkylcopper species have received considerable

• attention due to their unique properties in stereoselective allylic substitution. This review highlights recent advances in copper-catalyzed asymmetric allylic substitution reactions with chiral secondary alkylcopper species, encompassing several key strategies for their generation: stereospecific

• transmetalation of organolithium and organoboron compounds, copper hydride catalysis, and enantiotopic-group-selective transformations of 1,1-diborylalkanes. Detailed mechanistic insights into stereochemical control and current challenges in this field are also discussed. Keywords: allylic substitution; chiral

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

• groups, including an additional substitution on C-7, showed potent activity against nematodes. These acyl substituents, particularly the third cinnamoyl group on C-7, may significantly enhance the biological activity. This modification likely represents a key structural feature influencing its activity

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

• various substitution patterns in the aromatic ring, allowing a high variety of quinolines of general structure I and II. In a related work, quinolines of structure I (Scheme 8) could be obtained by similar reaction pathways. Jadhav et al. proposed a three-component cascade reaction between anilines

• reaction works very well for a wide variety of functional groups and substitution patterns in the aryl methyl ketone substrate, affording the desired heterocycle with good yields. Even heteroaryl methyl ketone and 1,3-dicarbonyl compounds work very well under these reaction conditions, leading to more

Deep-blue emitting 9,10-bis(perfluorobenzyl)anthracene

• Long K. San,
• Sebastian Balser,
• Brian J. Reeves,
• Tyler T. Clikeman,
• Yu-Sheng Chen,
• Steven H. Strauss and
• Olga V. Boltalina

Beilstein J. Org. Chem. 2025, 21, 515–525, doi:10.3762/bjoc.21.39

• higher selectivity with milder reaction temperatures. The weaker C(sp2)–Br bond is easier to cleave than a C(sp2)–H bond, resulting in a higher likelihood of radical substitution at those positions. To the best of our knowledge, there are no previous examples of perfluorobenzyl substitution of any PAH(Br

• ratio was found to be 1.74 (theoretical = 1.75), confirming the composition to be ANTH(BnF)2. Slow evaporation of a CH2Cl2 solution of 9,10-ANTH(BnF)2 at 2 °C afforded off-white plates suitable for X-ray diffraction. The structure shown in Figure 2 (top panel) confirmed the 9,10-substitution pattern

Unprecedented visible light-initiated topochemical [2 + 2] cycloaddition in a functionalized bimane dye

• Metodej Dvoracek,
• Brendan Twamley,
• Mathias O. Senge and
• Mikhail A. Filatov

Beilstein J. Org. Chem. 2025, 21, 500–509, doi:10.3762/bjoc.21.37

• with the Schmidt criteria for topochemical cycloaddition. Additionally, two other bimane derivatives with different substitution patterns were synthesized and investigated. Our findings suggest that functionalizing bimanes to redshift their absorption maxima into the visible-light spectrum provides a

Synthesis of N-acetyl diazocine derivatives via cross-coupling reaction

• Thomas Brandt,
• Pascal Lentes,
• Jeremy Rudtke,
• Michael Hösgen,
• Christian Näther and
• Rainer Herges

Beilstein J. Org. Chem. 2025, 21, 490–499, doi:10.3762/bjoc.21.36

• ]. Moreover, the parent diazocine is insoluble in water (precipitation in water/DMSO > 9:1). Substitution with polar substituents such as CH2NH2 provides water solubility, however, it does not restore the high Z → E conversion rates of the parent system in organic solvents, which is a disadvantage, since

• biochemical reactions usually take place in aqueous environments [13]. The substitution of one CH2 group in the CH2CH2 bridge by N–C(=O)–CH3 leads to an intrinsic water solubility of the N-acetyl diazocine 1 (Figure 1) [3]. Furthermore the photoconversion of 1 shows no significant drop in pure water in

• substitution. Substituents such as halogen atoms must be introduced into the N-acetyl diazocine structure during the synthesis of the building blocks. In the present work we start from mono- and dihalogenated N-acetyl diazocine 2–4 (Figure 2) and focus on the further derivatization via cross-coupling reactions

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

• Br(II) followed by subsequent deprotonation to generate radical B. A following disproportionation of radical B would lead to the formation of Br(III) species C (anodic oxidation cannot be fully excluded), which undergoes intramolecular SNAr-type substitution to form cyclic λ3-bromane 1a and

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

• 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

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

• glycosylation. Conventional glycosylation involves the ‘nucleophilic substitution’ of the leaving group at the sp3 anomeric centre of the donor moiety with a suitable carbohydrate or non-carbohydrate-based aglycon with the help of an electrophilic promoter to form the equatorial glycoside 7 or the axial

• pairs in glycosylation mechanisms was first reported by Rhind-Tutt and Vernon [44], and later reiterated by various authors, including the seminal graphical analysis of Lemieux and co-workers [45][46][47]. Thus, complete categorisation of the reaction in either of the subdomains of substitution reaction

• glycosylation reaction between the two extremes of substitution reactions enables the synthetic chemists to manoeuvre and design the coupling reactions according to the regio- and stereochemical demand. In chemical glycosylation, the role of protecting groups in directing the attack of the incoming nucleophile

Red light excitation: illuminating photocatalysis in a new spectrum

• Lucas Fortier,
• Corentin Lefebvre and
• Norbert Hoffmann

Beilstein J. Org. Chem. 2025, 21, 296–326, doi:10.3762/bjoc.21.22

• , which includes various aryl- and alkylboronates, showcasing its applicability across a range of chemical transformations. For example, phenylboronic acids with diverse substitution patterns (such as electron-donating and electron-withdrawing groups) were smoothly converted to the corresponding alcohols

• , making them more oxidizing. Extended conjugation in cyanins (e.g., 53 and 54) further increases their oxidizing nature at the ground state. Overall, both central substitution and extended conjugation play crucial roles in determining the redox behavior of these dyes. Cyanins with an amino group on the

Molecular diversity of the reactions of MBH carbonates of isatins and various nucleophiles

• Zi-Ying Xiao,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2025, 21, 286–295, doi:10.3762/bjoc.21.21

• Zi-Ying Xiao Jing Sun Chao-Guo Yan College of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou 225002, China 10.3762/bjoc.21.21 Abstract In this paper, the nucleophilic substitution reactions of various N- and P-containing nucleophiles to MBH carbonates of isatins were investigated

• ]. In the presence of a Lewis base, MBH carbonates of isatins can be easily converted to activated allylic ylides, which in turn can undergo allylic substitution and annulation reactions to give diverse 3-substituted and spirooxindole derivatives [36][37][38][39][40][41]. Inspired by these elegant

• synthetic methodologies and in continuation of our aim to develop domino reactions based on MBH carbonates of isatins for efficient construction of diverse polycyclic spiroindolinones [42][43][44][45][46][47][48][49][50][51][52], herein, we wish to report the nucleophilic substitution reactions of various N

Synthesis and characterizations of highly luminescent 5-isopropoxybenzo[rst]pentaphene

• Islam S. Marae,
• Jingyun Tan,
• Rengo Yoshioka,
• Zakaria Ziadi,
• Eugene Khaskin,
• Serhii Vasylevskyi,
• Ryota Kabe,
• Xiushang Xu and
• Akimitsu Narita

Beilstein J. Org. Chem. 2025, 21, 270–276, doi:10.3762/bjoc.21.19

• singlet (S1) state [21]. Notably, a dimer of BPP, 5,5'-bibenzo[rst]pentaphene (BBPP), exhibited an enhanced PLQY of 44% through intensity borrowing from its bright S2 state as well as intriguing symmetry-breaking charge transfer between two BPP units. Moreover, the substitution of BPP with two electron

Effect of substitution position of aryl groups on the thermal back reactivity of aza-diarylethene photoswitches and prediction by density functional theory

• Misato Suganuma,
• Daichi Kitagawa,
• Shota Hamatani and
• Seiya Kobatake

Beilstein J. Org. Chem. 2025, 21, 242–252, doi:10.3762/bjoc.21.16

• analysis of the thermal back reaction revealed activation parameters, highlighting how the substitution position of the aryl group affects the thermal stability. Additionally, density functional theory calculations identified M06 and MPW1PW91 as the most accurate functionals for predicting the thermal back

• calculations can be a powerful tool for molecular design. In this work, we newly synthesize various aza-diarylethene derivatives N3, N4, and I1–I4 with different substitution positions of the aryl group, and investigate their photochromic behaviors and thermal back reactivities as the data set for the

• ‡ and ΔS‡ values from the viewpoint of substitution position, when the aryl group is phenylthiophene (N1 and I1) or phenylthiazole (N2 and I2), both the ΔH‡ and the ΔS‡ values decreased by the change of the substitution position of the aryl group from N to I. In contrast, when the aryl group is

Heteroannulations of cyanoacetamide-based MCR scaffolds utilizing formamide

• Marios Zingiridis,
• Danae Papachristodoulou,
• Despoina Menegaki,
• Konstantinos G. Froudas and
• Constantinos G. Neochoritis

Beilstein J. Org. Chem. 2025, 21, 217–225, doi:10.3762/bjoc.21.13

• (hetero)aromatic, bulky and linear amines with different substitution patterns. The compounds 2–4 were purified by recrystallization and employed as such (Scheme 2). To our great delight, the heterocycles 2–4 could successfully be subjected to refluxing formamide under neat conditions, instantly yielding

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

• transformation relies on the catalysis with azolium precatalyst C12 (Scheme 11a). The reaction also allowed the synthesis of indol-derived bridged biaryls 35 (Scheme 11b). The proposed mechanism, supported by DFT calculations, comprises propargylic substitution towards Int-20 with NHC-derived enolate Int-19

• the azodicarboxylate as crucial to forming hydrogen bonds with the organocatalyst. Benzylation of this nitrogen or substitution of just one of the carboxylate groups led to no product being observed. A series of naphthylindoles 71 was tested for potential biological activity and showed promising

• importance of hydrogen on the amino or hydroxy groups, supposedly through the bonding with the catalyst. Substitution of these groups or their hydrogens led to either halted reaction or significantly reduced enantiopurity of the products. Expanding the scope of available azodicarboxylates 77 and aromatic

Emerging trends in the optimization of organic synthesis through high-throughput tools and machine learning

• Pablo Quijano Velasco,
• Kedar Hippalgaonkar and
• Balamurugan Ramalingam

Beilstein J. Org. Chem. 2025, 21, 10–38, doi:10.3762/bjoc.21.3

• , photoredox-catalytic, and nucleophilic aromatic substitution reactions, as well as in the two-step synthesis of cyclobutanone. The molecules synthesized under the optimal conditions are presented in Figure 6b, employing the stable noisy optimization by branch and fit (SNOBFIT) algorithm. SNOBFIT offers a

Synthesis, characterization, and photophysical properties of novel 9‑phenyl-9-phosphafluorene oxide derivatives

• Shuxian Qiu,
• Duan Dong,
• Jiahui Li,
• Huiting Wen,
• Jinpeng Li,
• Yu Yang,
• Shengxian Zhai and
• Xingyuan Gao

Beilstein J. Org. Chem. 2024, 20, 3299–3305, doi:10.3762/bjoc.20.274

• available 2-bromo-4-fluoro-1-nitrobenzene, featuring a noble-metal-free system, mild reaction conditions, and a good yield, especially for the final Cs2CO3-facilitated nucleophilic substitution (77–91% yield). The characterization data obtained from IR and NMR spectroscopy (1H, 13C, 19F, and 31P) as well as

• hand, we turned our attention to the synthesis of PhFlOP-based compounds through a Cs2CO3-facilitated nucleophilic substitution with substituted carbazoles as the nucleophiles (Scheme 2). For example, tert-butyl, bromo, carbazolyl, or phenyl substituents were introduced into the carbazoles. To our

Efficient synthesis of fluorinated triphenylenes with enhanced arene–perfluoroarene interactions in columnar mesophases

• Yang Chen,
• Jiao He,
• Hang Lin,
• Hai-Feng Wang,
• Ping Hu,
• Bi-Qin Wang,
• Ke-Qing Zhao and
• Bertrand Donnio

Beilstein J. Org. Chem. 2024, 20, 3263–3273, doi:10.3762/bjoc.20.270

• chains and derived from the classical triphenylene core self-assembling in columnar mesophases based on this paradigm. These mesogenic compounds were simply obtained in good yields by the nucleophilic substitution (SNFAr) of various types of commercially available fluoroarenes with the electrophilic

• substitution of the terminal phenyl ring with a pentafluorophenyl ring. Thus, as expected, they display a Colhex mesophase over large temperature ranges, with only small differences in the mesophase stability and transition temperatures. Furthermore, the presence of the terminal fluorophenyl group enables a

• subsequent second annulation, yielding a new series of extended polyaromatic mesomorphic compounds, i.e., 1,1',3,3',4,4'-hexafluoro-6,6',7,7',10,10',11,11'-octaalkoxy-2,2'-bitriphenylene (Gnm) which were found to display a Colrec mesophase. The specific nucleophilic substitution patterns of the Fn

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• -derived azadiene by H-bonding. This dual activation promotes a stereoselective addition of 3-chlorooxindole to the azadiene leading to intermediate A. The latter is also activated by the chiral guanidine and undergoes an intramolecular nucleophilic substitution which delivers the product 19b with the

• ketones 42 [37]. With this transformation polysubstituted cyclohexanes 43 bearing four consecutive stereocenters are afforded through efficient one-pot cyclization with good yields (43–95%) and with high enantioselectivities (80–97% ee) (Scheme 15). In general, 1-azadienes 14 with different substitution

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

• arene moieties. These observations confirmed the LUMO as an appropriate lobe for nucleophilic attack via the SN2 pathway (path 2), and confirmed the LUMO+1 as an appropriate lobe for substitution via reductive elimination (path 1). As such, neither mechanism could be immediately discarded, and we were