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

• /bjoc.21.45 Abstract Formaldehyde emerges as a cornerstone in multicomponent reactions, mainly prized for its robust reactivity. Yet, alongside these beneficial traits, this highly reactive C1-building block raises concerns, primarily regarding its toxicity. One notable issue is the challenge of

• of green MCRs due to its high reactivity under these conditions [7]. However, this reactivity also increases the potential for the formation of byproducts. Furthermore, formaldehyde is widely recognized to be toxic and is considered carcinogenic by the World Health Organization (WHO) both in solution

• phosphites can also undergo an addition to the C=O bond of the carbonyl component (Abramov reaction) giving α-hydroxy phosphonates 33 as byproducts (Scheme 26a) [72]. Competition between the two nucleophiles for the electrophilic carbonyl compound depends on their relative reactivity [74][77] and this lack

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

• ). Further details on this are available in the experimental section. This suggests that the reaction is topochemical, with the bimane’s reactivity dependent on its crystal packing, since no [2 + 2] cycloaddition product was seen in the spectrum. While the reaction may also depend on the reactivities of the

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

• mRNA domain, namely the preQ1 class-I riboswitch (preQ1-I) from Thermoanaerobacter tengcongensis. By rigorously analyzing the high-resolution structures available for this ligand–RNA complex, the approach exploits the natural, sequence-inherent reactivity hotspots of RNA and thus avoids the use of

• highly electrophilic warheads otherwise typically employed in RNA-small molecule crosslinking [18][19][20][21]. Instead, primary alkyl halides (or mesylates, Scheme 1, in particular compounds 3a, 3b and 4c) were found to be potent yet mild alkylators that minimize off-target reactivity, while providing

• -diaminopyrimidin-4(3H)-one to afford preQ0 (7), as originally reported by Townsend et al. [30]. The next step, namely the reduction of the nitrile moiety by hydrogenation is critical and notoriously difficult due to the low reactivity of this group in preQ0 [26]. We solved this problem by applying strongly acidic

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

• Chimiche e Geologiche, Università degli Studi di Cagliari, Cittadella Universitaria, SS554 bivio per Sestu, 09042-Monserrato (CA), Italy CIRCC (Interuniversity Consortium Chemical Reactivity and Catalysis), via Celso Ulpiani 27, 70126 Bari, Italy Department of Chemistry, Life Sciences and Environmental

• photon by a molecule causes the reorganization of the electron density around the atoms and unlocks unique reactivity modes [2][3]. In photochemical methods, light is directly absorbed by a functional group embedded in the substrate and can be exploited for example to cleave bonds or trigger

• spectroscopy (Scheme 1). During the reaction progress, the C=C bonds of bpe ligands undergo pedal-like motion prior to photodimerization [63]. For the single-crystal irradiation, the slow reactivity can be attributed to the hindered pedal motion in the single crystals, likely due to the presence of

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

• -substituted 1d could be also obtained under the developed conditions. Unsymmetrically substituted 4e and monosubstituted dibromides 4f,g demonstrated reactivity similar to that of their symmetrical analogues 4b,c with exception of the mono-MeO-substituted dibromide 4h. Notably, the presence of two stabilizing

• substrates that do not form the desired electrochemical oxidation product see Supporting Information File 1, Scheme S1). A series of control experiments was performed to rationalize the observed reactivity trends (Scheme 2). The measured redox potentials EP/2 for 2,2'-dibromo-1,1'-biphenyls 4a–g (from 1.77 V

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

• substrate reactivity [64]. Cyclodextrins, cucurbiturils, cavitands, and calixarenes are representative [64][65][66][67][68][69][70], and typical features of these macrocycles are high symmetry and a hydrophobic cavity with polar edge groups. They tend to be synthesized as covalent cyclic oligomers in

• host catalysis – (i) using the host as a “protecting group” to direct reactivity external to the host [187][346], and (ii) confinement of a transition-metal catalyst to take advantage of the restricted environment of the host [51][52] – neither of which resembles the enzyme-like possibility of a true

• active site (binding a substrate in an orientation that directs internally catalyzed reactivity) [347][348]. The examples of cavities with functionality discussed above, from Cram’s “full serine protease model” [87], to MOCs with flexible peripheral groups [349], to frameworks with internal proline

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

• the cases (exception depicted for perbenzoylated SBox glycosides exhibiting superarmament [79] proving to be more reactive than the analogous perbenzylated donors) thereby reducing the reactivity of the glycosyl donors. The challenge is to activate the ester-protected glycosyl donor and to implement

• ]. However, the concept of ‘armed–disarmed’ protecting groups is often misleading and it has now been accepted that the protecting groups in the far end of the glycoside donor also contribute to the reactivity and stereoselectivity of the produced glycoside, which will be broadly illustrated in the following

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

• ; Introduction 1,2-Benzoquinones represent unique building blocks for various classes of heterocyclic systems. Their structure depends on the reactivity of the initial heterocycles and 1,2-benzoquinones, as well as on the reaction conditions. In the series of 2-methylquinolines [1], 2-methylquinoxalines [2], 2

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

• or side reactivity in a scope of around 50 examples with yields ranging from 27 to 97 % compared to the use of blue-light (Scheme 3a) [20]. In this way, T. Rovis et al. have exploited their photocatalytic system on the functionalization of drug-like scaffolds with moderate to good yields (Scheme 3b

• . While transition metals such as copper, palladium, cobalt, and nickel are well-established in catalyzed cross-coupling reactions, J. Cornella et al. have highlighted the reactivity of main-group elements like bismuth, which can mimic transition-metal behavior through oxidative addition. In their recent

• study, the authors have developed a complementary ground-state- and excited-state-driven aryl oxidative addition platform based on an N,C,N-bismuthinidene complex, showing the unique capacity of this main-group element to engage in reactivity typically associated with d-block metals [21]. The study

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

• an indole motif with a ketone and a γ-lactam moiety occur in numerous natural substances [1][2][3][4]. Isatins have many interesting aspects in organic reactions and potential applications. The versatile reactivity of isatins used both as an electrophiles and nucleophiles and their easy availability

• reactions of isatins with alkyl acrylates, acrylonitrile, and other activated alkenes [26][27][28][29]. Due to the stronger electron-withdrawing effect of the oxindole motif, MBH carbonates of isatins showed higher reactivity than that of the normal MBH carbonates of normal ketones [30][31][32][33][34][35

• promoter is needed in the reaction, which is assumed to be due to the much higher reactivity of MBH maleimides of isatins compared to the above-mentioned MBH nitriles and formats of isatins. The single crystal structures of the compounds 5a and 5j were successfully determined (Figure 1 and Figure 2). From

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

• adducts of formaldehyde condensation are formed under milder conditions and are highly reactive, which is important for further synthetic transformations. However, due to the high carbonyl reactivity of formaldehyde, its interaction with active methylene compounds is often complicated by polycondensation

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

• reactivity, closely matching the experimental data. These findings offer valuable insights for the design of advanced photochromic materials with tailored thermal and photophysical characteristics. Keywords: aza-diarylethene; DFT calculation; photochromism; prediction; thermal back reactivity; Introduction

• and predict the thermal reactivity of T-type molecules, and many researchers have made their efforts to control the thermal reactivity in various molecular systems by performing chemical modifications on the molecular structures [46][47][48]. For instance, Aprahamian and co-workers reported that

• modulate the thermal reactivity in each molecular system is very important. Recently, we have developed aza-diarylethenes N1 and N2 shown in Scheme 1, in which one of the reactive carbons of the diarylethene is replaced by nitrogen, as a new class of T-type photochromic compounds [56][57]. Aza

Visible-light-promoted radical cyclisation of unactivated alkenes in benzimidazoles: synthesis of difluoromethyl- and aryldifluoromethyl-substituted polycyclic imidazoles

• Yujun Pang,
• Jinglan Yan,
• Nawaf Al-Maharik,
• Qian Zhang,
• Zeguo Fang and
• Dong Li

Beilstein J. Org. Chem. 2025, 21, 234–241, doi:10.3762/bjoc.21.15

• . Furthermore, terminal olefins with varying chain lengths also reacted successfully, resulting in 5-membered and 7-membered cyclized products (3l–p) with yields between 44% and 66%. The lower yields in these cases might be due to the low reactivity of the intermediate C (Scheme 3), which may have made it less

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

• chemistry by using specific, suitably functionalized MCR scaffolds. This positions formamides as versatile, synthetic hubs towards privileged scaffolds and high-end chemicals. Over the years, the reactivity of formamide has been widely explored in heterocyclic chemistry, but it has only recently started to

Dioxazolones as electrophilic amide sources in copper-catalyzed and -mediated transformations

• Seungmin Lee,
• Minsuk Kim,
• Hyewon Han and
• Jongwoo Son

Beilstein J. Org. Chem. 2025, 21, 200–216, doi:10.3762/bjoc.21.12

• lactams in high yields and excellent enantioselectivities (2a, 2b, and 2d). It was observed that the steric environment affected both reactivity and enantioselectivity (2c). Six-membered lactams featuring propargylic (2e) and alkenyl (2f) motifs were also obtained with excellent regioselectivity and

• -triazole analogues 6. Both dioxazolones 4 and N-iminoquinolinium ylides 5 demonstrated excellent tolerance in this transformation. Notably, electron-rich dioxazolones exhibited slightly higher reactivity. The proposed catalytic cycle for the copper-catalyzed synthesis of 1,2,4-triazole derivatives is

• dioxazolone bearing a phenyl group showed no reactivity toward benzoyl amidine under the optimized reaction conditions. Instead, the authors employed a less bulky copper iodide catalyst in the absence of phosphine, successfully affording aryloyl amidine 10f. Furthermore, the electron-rich ethynylanisole

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

• reactions, particularly in controlling the high reactivity and selectivity of radical intermediates [13][14]. Early studies on copper-mediated radical reactions, such as Julia’s work on radical cyclization reaction [15], along with advancements in dimerization [16][17], oxidative cleavage [18][19], and

• electron transfer to the metal catalyst without the need for chemical redox agents, thus providing milder and more sustainable reaction conditions (Figure 2) [32]. Electrochemical reactions can be performed at low potentials, thereby suppressing side reactions, and chemoselectivity and reactivity can be

• achieved by precisely controlling the potential. Additionally, the merging of electrochemistry and transition-metal catalysis offers advantages in controlling substrate activation, intermediate reactivity, and bond formation, as well as facilitating asymmetric transformations. As a result, electrochemical

Nickel-catalyzed cross-coupling of 2-fluorobenzofurans with arylboronic acids via aromatic C–F bond activation

• Takeshi Fujita,
• Haruna Yabuki,
• Ryutaro Morioka,
• Kohei Fuchibe and
• Junji Ichikawa

Beilstein J. Org. Chem. 2025, 21, 146–154, doi:10.3762/bjoc.21.8

• distinct aryl groups onto a benzofuran ring through orthogonal coupling reactions, exploiting the reactivity difference between C–F and C–Br bonds (Scheme 4). Using a palladium catalyst, 5-bromo-2-fluorobenzofuran (1e) was coupled with [4-(trifluoromethyl)phenyl]boronic acid (2g). In this reaction, only

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

• behavior or reactivity properties. The ambiguity related to the role of Cu(OTf)2 is particularly relevant for cycloaddition reactions, where it is even more difficult to justify the activation of the copper species as a Lewis acid or metal catalyst [12][13][14]. The reaction mechanism involved can be ionic

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

• %. An extensive study on the reactivity of o-naphthoquinones 117 and 122 with 2-naphthylamines, 2-naphthols (118, 120), and indoles 123 was done in 2019 (Scheme 37) [65]. Four organocatalysts ((S)-C23, C31, C32, (R)-C23) proved the most efficient, and stereoinformation was effectively transferred in all

• indole nitrogen in control experiments led to halted reactivity or loss of enantiocontrol. These results suggest the importance of hydrogen bonding between the NH group and the organocatalyst. Bisindoles 142 reacted with ninhydrin-derived 3-indoylmethanol 143 in the presence of the CPA (S)-C22 to afford

• just one nitrogen resulted in retarded or halted reactivity. The combination of 2-naphthols 151 and alkynylhydroxyisoindolinones 152 in the presence of two chiral Brønsted acids C35 and C36 provided axially chiral isoindolinones 153 (Scheme 45) [73]. The optimized reaction conditions led to the handful

Synthesis of acenaphthylene-fused heteroarenes and polyoxygenated benzo[j]fluoranthenes via a Pd-catalyzed Suzuki–Miyaura/C–H arylation cascade

• Merve Yence,
• Dilgam Ahmadli,
• Damla Surmeli,
• Umut Mert Karacaoğlu,
• Sujit Pal and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2024, 20, 3290–3298, doi:10.3762/bjoc.20.273

• ). Finally, due to our interest in the structural features and chemistry of 1,8-dihydroxynaphthalene (1,8-DHN) [48][49], we were curious to check the reactivity of the previously unknown boronic ester 17d, which was prepared in one step from thiophene-3-ylboronic acid (17a) and 1,8-DHN [50]. Note that

• %, Table 2, entry 4). Afterwards, we sought to examine the reactivity of six-membered aromatic nitrogen heterocycles. The reactions of (2-methoxypyridin-3-yl)boronic acid with the dihalonaphthalenes 12 and 14 afforded substituted azafluoranthenes 15f and 15g in 90 and 51% yields, respectively (Table 2

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

• Beatriz Dedeiras Catarina S. Caldeira Jose C. Cunha Clara S. B. Gomes M. Manuel B. Marques LAQV-REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, NOVA FCT , 2829-516 Caparica, Portugal 10.3762/bjoc.20.272 Abstract The reactivity of our recently disclosed hypervalent iodine

• 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

• reactivity, yielding numerous derivatives with wide applications [2][3][4][6][7][8]. Their enhanced stability, compared to other HIRs, is due to: (i) the molecular geometry, which allows better overlap between the non-bonding electrons of the central iodine atom and the π-orbitals of the aromatic ring [2][9

Giese-type alkylation of dehydroalanine derivatives via silane-mediated alkyl bromide activation

• Perry van der Heide,
• Michele Retini,
• Fabiola Fanini,
• Giovanni Piersanti,
• Francesco Secci,
• Daniele Mazzarella,
• Timothy Noël and
• Alberto Luridiana

Beilstein J. Org. Chem. 2024, 20, 3274–3280, doi:10.3762/bjoc.20.271

• approaches have also gained widespread attention for their unique advantages in these transformations [4]. Radical chemistry often exhibits complementary reactivity to two-electron pathways and can be performed with high selectivity, atom economy, and functional group tolerance [5]. A well-known radical

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

• with the case of 1a. The reactivity toward the palladium-catalyzed cyclization was thus shown as 3 ≈ 1a >> 1b > 1c. The related trend was also observed in the reaction of phenanthroline monoamide 5a and diamide 5b. The reaction of 5a afforded the cyclized product in 51% yield, which contrasted with our

• 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

• leading to the synthesis of spirooxindole derivatives 6 bearing a thiourea moiety in high yields (91–97%), and with good to excellent diastereoselectivities (10:1–20:1 dr) and enantioselectivities (61–96%) (Scheme 2). Furthermore, the authors also investigated the reactivity of ketimines and dienimines

• straightforward methodology which enables the synthesis of structurally distinct N-heterocycles, which are difficult to access by other methodologies. Although in recent years a number of studies have been reported, further novel transformations are likely to be reported in the future. Reactivity of α,β

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

• ]. As such, the reaction has been used extensively throughout drug discovery [20][21], chemical biology [22][23], and materials science [24][25][26][27]. Orthogonal alkyne reactivity can also be observed under certain systems [28][29][30]. The reaction typically uses a Cu(II) pre-catalyst, which is

• reactivity compared to other alkynes, which typically require much shorter reaction times. Extending the reaction time provided a higher conversion to the product 14. Yields were observed to be greater for aryl azides (e.g., 4 vs 6). Heterocycles such as pyridine (1), pyrimidine (10), phenothiazine (11), and