Recent advances in amidyl radical-mediated photocatalytic direct intermolecular hydrogen atom transfer

• Hao-Sen Wang,
• Lin Li,
• Xin Chen,
• Jian-Li Wu,
• Kai Sun,
• Xiao-Lan Chen,
• Ling-Bo Qu and
• Bing Yu

Beilstein J. Org. Chem. 2025, 21, 1306–1323, doi:10.3762/bjoc.21.100

• require electrophilic heterocycles. These limitations hinder the broader application of such systems. Alexanian’s group modified amidyl radical precursors by incorporating halogen atoms, transforming them into bifunctional reagents. The HAT component of amidyl radical precursors was facilitated by amidyl

• area. Switchable amidyl radicals provide an effective toolkit for completing hydrogen atom transfer processes. Transitioning from noble metal photocatalysts to organic photocatalysts and from HAT reagents to bifunctional reagents, these remarkable photocatalytic systems have inspired innovations across

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

• in elucidating the mechanism by which these bifunctional compounds act as powerful catalysts [21][22][23][24][25][26][27][28][29]. Since Ishihara disclosed the crucial role of calcium in many purportedly purely organocatalytic BINOL phosphate-catalyzed reactions [30][31], several asymmetric synthesis

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

• 14 (Figure 2). Synthesis of a bifunctional Pepper dye Encouraged by the efficient attachment of the bromo- and mesyloxypropyl-modified HBC fluorophores to the Pepper aptamer, we generated a bifunctional HBC ligand with a second handle that is available for bioorthogonal reactions. The original

• usefulness of this type of bifunctional fluorescent ligands in RNA affinity purification has recently been demonstrated by our group [11]. Conclusion Covalent fluorescent light-up aptamers (coFLAPs) are opening new avenues for RNA imaging [11]. In this work, we describe robust synthetic routes for twelve HBC

• bromoalkyl HBC derivatives 7, 8, and 9. Synthesis of the HBC ether derivative 11. Derivatization of the HBC fluorophore 5 to generate handles with distinct electrophilic groups. Synthesis of mesylated HBC fluorophores 16, 17, and 18. Synthesis of the bifunctional HBC fluorophore 22. For an application of 22

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

• to pyrazolones occurred. The analogous process using hydroxylamine allowed us to prepare the similar isoxazolone with allomaltol fragment. Extensive studies have enabled the development of a straightforward approach to novel bifunctional products containing both allomaltol and pyrazolone cores. The

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

• [32]. Then, we increased the reaction scale to 0.2 mmol and obtained similar results (Table 1, entry 13). At this point, we decided to explore the use of a bifunctional organocatalyst in order to improve the yield. When squaramide SQ-1 was used as a catalyst, we observed a similar yield and

• diastereoselectivity after 24 h of reaction (61% yield and 7:1 dr, Table 1, entry 14). By lowering the reaction temperature to 50 °C using the same catalyst (Table 1, entry 15), the yield of the reaction increased slightly to 73% in 24 hours. Disappointingly, the bifunctional thiourea THIO-1 gave a lower yield 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

• , therefore, that for redistribution penalties to be lessened, the equal and opposite stabilization must be granted to that same space. This is the basis of bifunctional/dual activation, as shown in Figure 1. Since very few reported supramolecular cavity designs provide bifunctional activation, cavity

• 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

• organocatalysts [222][234] all suffer from the same limitation: they all fail to rigidly organize sufficient bifunctional groups to obtain clear transition-state binding – a hallmark of enzymes and organocatalysts [107][180]. Strategy towards organocatalytic organic cages: My laboratory has levied the following

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

Intramolecular C–H arylation of pyridine derivatives with a palladium catalyst for the synthesis of multiply fused heteroaromatic compounds

• Yuki Nakanishi,
• Shoichi Sugita,
• Kentaro Okano and
• Atsunori Mori

Beilstein J. Org. Chem. 2024, 20, 3256–3262, doi:10.3762/bjoc.20.269

• previous result for the cyclization of 5b to afford the doubly cyclized product 6b (reported yield: 85% [23]), suggesting that the superior reactivity was found for bifunctional bisamides compared to monoamides. It was also found that the reaction also is applicable to a carbocyclic amide derivative. When

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

• -raising activation (amine-based catalysis and N-heterocyclic carbenes), and iii) LUMO-lowering and HOMO-raising activation (bifunctional thioureas and squaramides). Due to the ubiquitous nature of non-covalent interactions in organic systems, they can play a decisive role in asymmetric transformations [15

• covered in this review are hydrogen-bond donors such as thioureas and squaramides, Brønsted bases such as tertiary amines, and Brønsted acids such as chiral phosphoric acids. As depicted in Figure 4, a bifunctional squaramide is able to activate both an α,β-unsaturated imine through hydrogen bonding with

• reviews [17][18]. Review Hydrogen bond donors: bifunctional thioureas and squaramides The use of bifunctional catalysts is commonplace in organocatalyzed transformations [19][20][21][22][23]. These catalysts are able to activate an electrophile and a nucleophile simultaneously and in IEDADA reactions they

Germanyl triazoles as a platform for CuAAC diversification and chemoselective orthogonal cross-coupling

• John M. Halford-McGuff,
• Thomas M. Richardson,
• Aidan P. McKay,
• Frederik Peschke,
• Glenn A. Burley and
• Allan J. B. Watson

Beilstein J. Org. Chem. 2024, 20, 3198–3204, doi:10.3762/bjoc.20.265

• further diversification of the triazole products, including chemoselective transition metal-catalysed cross-coupling reactions using bifunctional boryl/germyl species. Keywords: chemoselectivity; click chemistry; copper; germanium; triazole; Introduction Since its inception, click chemistry has been

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• single step. The oxazepine scaffold can be easily accessed using the Ugi four-component reaction. By modifying this scaffold, the researchers aimed to reduce the hydrogen-bond donating properties. The Passerini reaction, employing bifunctional salicylaldehydes and isocyanides successfully yielded

Advances in the use of metal-free tetrapyrrolic macrocycles as catalysts

• Mandeep K. Chahal

Beilstein J. Org. Chem. 2024, 20, 3085–3112, doi:10.3762/bjoc.20.257

• active groups for a variety of substrates, making their use as supramolecular organocatalysts based on bifunctional activation mechanism (hydrogen-bonding/Lewis basicity) highly promising. At the same time, additional functional groups that are required for the catalysis can be easily installed on the

• pyrrolic N/N–H moieties [58][59][60]. Overall, these alterations provide a versatile toolkit for tailoring porphyrin properties for various applications. In 2017, Senge and co-workers, reported the first example of using metal-free tetrapyrrolic porphyrins as bifunctional organocatalysts, confirming that

• one remaining –NH group is catalytically active while both tri- and tetraalkylated analogues 40 and 41, without an –NH unit, are not. Further, the authors performed 1H NMR experiments with a different substrate:macrocycle ratio and suggested a bifunctional reaction mechanism involving both inner amine

Synthesis of the 1,5-disubstituted tetrazole-methanesulfonylindole hybrid system via high-order multicomponent reaction

• Cesia M. Aguilar-Morales,
• América A. Frías-López,
• Nadia V. Emilio-Velázquez,
• Alejandro Islas-Jácome,
• Angelica Judith Granados-López,
• Jorge Gustavo Araujo-Huitrado,
• Yamilé López-Hernández,
• Hiram Hernández-López,
• Luis Chacón-García,
• Jesús Adrián López and
• Carlos J. Cortés-García

Beilstein J. Org. Chem. 2024, 20, 3077–3084, doi:10.3762/bjoc.20.256

• trifluoroethanol as the solvent and at room temperature [23][24][25][26]. In the initial reaction, propargylamine served as a bifunctional reagent, with the primary amine group participating in the first step and the terminal alkyne promoting the subsequent heteroannulation. (Scheme 2). As observed in our previous

• trifluoroethanol to Et3N for the subsequent catalysis). Thus, this protocol enabled a straightforward and rapid synthesis of highly 2-substituted indoles under mild reaction conditions, highlighting the versatility of propargylamine as a bifunctional reagent in post-Ugi-azide transformations. Our group pioneered

• reaction is utilized as a post-Ugi-azide reaction, using propargylamine as a key bifunctional reagent. The results of cytotoxic activity were moderate. However, the information obtained from this study, together with that obtained with previously described analogs, provide important information for

C–C Coupling in sterically demanding porphyrin environments

• Liam Cribbin,
• Brendan Twamley,
• Nicolae Buga,
• John E. O’ Brien,
• Raphael Bühler,
• Roland A. Fischer and
• Mathias O. Senge

Beilstein J. Org. Chem. 2024, 20, 2784–2798, doi:10.3762/bjoc.20.234

• independent faces and trap anions such as pyrophosphate [15]. Saddle-shaped porphyrins have also been exploited by researchers for the use in organocatalysis as bifunctional system [16][17]. Dodecasubstitution of porphyrin, as seen in Figure 1, often results in saddle-shaped distortion; however, ruffled [18

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• oxidation strategy to obtain α-chlorosulfoxides from sulfides using hydrochloric acid as a bifunctional reagent [22]. This strategy accommodates a broad range of substrates and offers high diastereoselectivity and regioselectivity. Several LSF modifications of amino acids and pharmaceutical derivatives

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• [39] developed a direct, highly enantioselective three-component reaction between aromatic acetals, BocNH2, and various 2-monosubstituted or 2,3-disubstituted allyltrimethylsilanes in the presence of 10 mol % of triethylsilyl triflate (TESOTf) and 10 mol % of the chiral bifunctional thiourea catalyst

• stereospecific synthesis of γ- and γ,δ-substituted homoallylic amines by a three-component reaction between an aryl acetal, BocNH2 carbamate and a 2,3-disubstituted allylsilane, in presence of the triflate-assisted bifunctional HBD/πAr-Ar catalyst [39]. Catalytic cycle for the three-component allylation with HBD

Stereoselective mechanochemical synthesis of thiomalonate Michael adducts via iminium catalysis by chiral primary amines

• Michał Błauciak,
• Dominika Andrzejczyk,
• Błażej Dziuk and
• Rafał Kowalczyk

Beilstein J. Org. Chem. 2024, 20, 2313–2322, doi:10.3762/bjoc.20.198

• by extended reaction times, sometimes up to 168 hours. An intriguing example involves the use of a bifunctional primary amine-sulfonamide catalyst, which activates benzylideneacetone towards dibenzyl malonate, with the presence of water accelerating the reaction [25]. An alternative approach, where

• Discussion Based on our previous experiences with low-reactive Michael acceptors [29], initial attempts were carried out using bifunctional squaramides, derivatives of cinchona. However, up to 45% yield of the desired product was obtained with poor enantioselectivity (14%, Scheme 2). Considering the

• product with 93% ee after 24 h, while the bifunctional primary amine-thiourea catalysts (system B) required 4 days to provide an adduct with similar enantioselectivity. Prolonged reaction time is in general the innate nature of organocatalytic reactions employing iminium activation approaches. With the

Catalysing (organo-)catalysis: Trends in the application of machine learning to enantioselective organocatalysis

• Stefan P. Schmid,
• Leon Schlosser,
• Frank Glorius and
• Kjell Jorner

Beilstein J. Org. Chem. 2024, 20, 2280–2304, doi:10.3762/bjoc.20.196

• [107] (Figure 11B). Werth and Sigman [127] investigated multiple nucleophilic additions to nitroalkenes, catalysed by bifunctional hydrogen bond donors, observing good correlations to new bi-functional donors, new nucleophiles, new electrophiles and even similar cascade-type reactions. In the authors

Computational toolbox for the analysis of protein–glycan interactions

• Ferran Nieto-Fabregat,
• Maria Pia Lenza,
• Angela Marseglia,
• Cristina Di Carluccio,
• Antonio Molinaro,
• Alba Silipo and
• Roberta Marchetti

Beilstein J. Org. Chem. 2024, 20, 2084–2107, doi:10.3762/bjoc.20.180

Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications

• Matteo Gasparetto,
• Balázs Fődi and
• Gellért Sipos

Beilstein J. Org. Chem. 2024, 20, 1922–1932, doi:10.3762/bjoc.20.168

• crucial function in many biological processes. Due to their bifunctional character, they have been also used for combinatorial chemistry purposes, such as the preparation of DNA-encoded chemical libraries. We developed a practical synthesis for α-heteroaryl-α-amino acids starting from an array of small

• bifunctional building blocks (BBs) can quickly increase the diversity of these molecular libraries [6]. Hence, DEL practitioners constantly seek access to novel building blocks [7]. Amino acids (AAs) are vital motifs in the domain of biochemistry, serving as the foundational unit for peptides and proteins

• , while also holding a crucial function in many biological processes [8]. Non-canonical amino acids (NCAs) are widely used in medicinal chemistry [9]. Not surprisingly, they also find broad use as bifunctional building blocks (BBs) for DELs. In an early example, an 800-million-members DEL utilized Fmoc

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• excellent yields (71–89%). Dömling et al. have used glyoxal dimethyl acetal as orthogonal bifunctional monoprotected aldehyde to synthetize GBB dimers as potential fluorophores. More details are given in chapter 5 [43]. The GBB reaction can be exploited also in the late-stage functionalization of natural

• provide the ammonium 77. The intermediate 77 underwent Steven rearrangement to give a bridged polyheterocycle 78 in 28% yield. Unlike the previous examples, Jeong et al. [60] developed a cascade reaction by installing the additional ring prior to the GBB reaction (Scheme 26). The bifunctional 2-(2

Chiral bifunctional sulfide-catalyzed enantioselective bromolactonizations of α- and β-substituted 5-hexenoic acids

• Sao Sumida,
• Ken Okuno,
• Taiki Mori,
• Yasuaki Furuya and
• Seiji Shirakawa

Beilstein J. Org. Chem. 2024, 20, 1794–1799, doi:10.3762/bjoc.20.158

• without substituents on the carbon–carbon double bond have remained a formidable challenge. To address this limitation, we report herein the asymmetric bromolactonization of 5-hexenoic acid derivatives catalyzed by a BINOL-derived chiral bifunctional sulfide. Keywords: asymmetric catalysis

• remained a formidable challenge in the field of catalytic asymmetric synthesis (Scheme 1b) [23][24][25]. To address this limitation, we have investigated the use of BINOL-derived chiral bifunctional sulfide catalysts, which were developed by our group [10], in asymmetric bromolactonizations of α

• bifunctional sulfide (S)-1 [26][27][28][29][30][31]. To further demonstrate the utility of our chiral bifunctional sulfide catalysts in challenging halolactonizations, we next turned our attention to the asymmetric bromolactonizations of 5-hexenoic acid derivatives 2 for the synthesis of optically active δ

Primary amine-catalyzed enantioselective 1,4-Michael addition reaction of pyrazolin-5-ones to α,β-unsaturated ketones

• Pooja Goyal,
• Akhil K. Dubey,
• Raghunath Chowdhury and
• Amey Wadawale

Beilstein J. Org. Chem. 2024, 20, 1518–1526, doi:10.3762/bjoc.20.136

• -covalent catalysis via bifunctional hydrogen-bonding organocatalysts. The C-4 nucleophilicity of pyrazolin-5-ones was also explored in enantioselective reactions with α,β-unsaturated carbonyl compounds through covalent catalysis with chiral amine-based catalysts; however, it has achieved limited success

Challenge N- versus O-six-membered annulation: FeCl₃-catalyzed synthesis of heterocyclic N,O-aminals

• Giacomo Mari,
• Lucia De Crescentini,
• Gianfranco Favi,
• Fabio Mantellini,
• Diego Olivieri and
• Stefania Santeusanio

Beilstein J. Org. Chem. 2024, 20, 1412–1420, doi:10.3762/bjoc.20.123

• of diversity-oriented synthesis of N-heterocycles via sequential multicomponent approaches, we envisioned that α-aminoacetals could act as bifunctional building blocks along with 1,2-diaza-1,3-diene (DD) coupling partners [22][23], in obtaining functionalized N-aminohydrazones as key intermediates

Hypervalent iodine-catalyzed amide and alkene coupling enabled by lithium salt activation

• Akanksha Chhikara,
• Fan Wu,
• Navdeep Kaur,
• Prabagar Baskaran,
• Alex M. Nguyen,
• Zhichang Yin,
• Anthony H. Pham and
• Wei Li

Beilstein J. Org. Chem. 2024, 20, 1405–1411, doi:10.3762/bjoc.20.122

• , which then partitions into an ion pair suitable for olefin activation, followed by the addition of the bifunctional anionic carbamate (Scheme 1c). Our hypothesis here aims to directly access the reactivity of the cationic hypervalent iodine catalyst through an initial activation first, which we reason

• hypervalent iodine catalyst. The cationic hypervalent iodine catalyst could then activate the olefin to allow the addition of bifunctional nucleophiles such as an amide to achieve an overall olefin oxyamination process. We have previously reported a series of iodide-catalyzed processes, in which the

• bifunctional amide nucleophiles (Scheme 1e). Results and Discussion Our studies here focused on the development of hypervalent iodine-catalyzed amide and alkene coupling reaction [53][54][55]. In this case, we started with styrene (1) and benzamide (2) as the standard substrates. Using iodotoluene A as the