The high potential of methyl laurate as a recyclable competitor to conventional toxic solvents in [3 + 2] cycloaddition reactions

• Ayhan Yıldırım and
• Mustafa Göker

Beilstein J. Org. Chem. 2025, 21, 2389–2415, doi:10.3762/bjoc.21.184

• for the preparation of such cyclic compounds and/or their fused cyclic systems typically necessitate the use of toxic solvents, including chloroform, benzene, toluene etc. [32][53][54][55][56][57][58][59]. Indeed, the selection of conventional organic solvents, including benzene, toluene and

• ADMETLab 3.0 platform [87] are illustrated in Figure 2a. Conversely, the oral toxicity values of methyl laurate, in conjunction with toluene and chloroform – two conventional solvents that are commonly employed in [3 + 2] cycloaddition reactions were calculated with ProTox 3.0 (a webserver for the

• , the conventional solvents that are typically employed as reaction media encompass a range of options, including tetrahydrofuran (THF) (a problematic solvent, p), dioxane (considered hazardous, h), benzene (designated as highly hazardous, hh), toluene (p), chloroform (hh), acetonitrile (p), sulfolane

Comparative analysis of complanadine A total syntheses

• Reem Al-Ahmad and
• Mingji Dai

Beilstein J. Org. Chem. 2025, 21, 2334–2344, doi:10.3762/bjoc.21.178

• synthesis [Pd(OAc)2, t-Bu2MePHBF4, Cs2CO3, and CsOPiv in toluene at 130 °C] was utilized to afford the C–H arylation in 78% yield with a 1:4 ratio of 68/69 [36]. Subsequent reduction of the pyridine N-oxide with Pd(OH)2/C and H2 followed by acidic Boc removal completed their total synthesis of complanadine

Pathway economy in cyclization of 1,n-enynes

• Hezhen Han,
• Wenjie Mao,
• Bin Lin,
• Maosheng Cheng,
• Lu Yang and
• Yongxiang Liu

Beilstein J. Org. Chem. 2025, 21, 2260–2282, doi:10.3762/bjoc.21.173

• 1,5-enynes 1 as substrates involving alkyne alkoxylation and dienol ether aromaticity-driven processes (Scheme 2) [8]. The reaction pathway was decisively influenced by the choice of solvent. Under gold catalysis, with toluene as the solvent and 2 equiv of methanol serving as the nucleophile, the

Thiadiazino-indole, thiadiazino-carbazole and benzothiadiazino-carbazole dioxides: synthesis, physicochemical and early ADME characterization of representatives of new tri-, tetra- and pentacyclic ring systems and their intermediates

• Gyöngyvér Pusztai,
• László Poszávácz,
• Anna Vincze,
• András Marton,
• Ahmed Qasim Abdulhussein,
• Judit Halász,
• András Dancsó,
• Gyula Simig,
• György Tibor Balogh and
• Balázs Volk

Beilstein J. Org. Chem. 2025, 21, 2220–2233, doi:10.3762/bjoc.21.169

• conditions. Finally, we were able to achieve the Fischer cyclization of compounds 7a–j by using p-toluenesulfonic acid monohydrate as catalyst in boiling toluene (method A, step 2) [26][27]. On the other hand, the one-pot synthesis of target compounds 3a–j starting from hydrazino derivatives 5a,b was

• 1) afforded hydrazones (E)-9a,b. According to LC–MS, only the (E) isomers were present in the reaction mixtures and in the crude products. Hydrazones (E)-9a,b were then cyclized by refluxing in toluene in the presence of p-toluenesulfonic acid monohydrate (method A, step 2). It is noteworthy that

• C17H18N4O2S, 342.1156; found, 342.1151. General methods for the synthesis of compounds 3a–j and 10a,b. Method A, step 2 [26][27]: A suspension of the corresponding crude hydrazone 7 or 9 (100 mg) and p-TsOH monohydrate (1.80 equiv) in toluene (1 mL) was refluxed until the starting material was consumed. Then

C2 to C6 biobased carbonyl platforms for fine chemistry

• Jingjing Jiang,
• Muhammad Noman Haider Tariq,
• Florence Popowycz,
• Yanlong Gu and
• Yves Queneau

Beilstein J. Org. Chem. 2025, 21, 2103–2172, doi:10.3762/bjoc.21.165

α-Ketoglutaric acid in Ugi reactions and Ugi/aza-Wittig tandem reactions

• Vladyslav O. Honcharov,
• Yana I. Sakhno,
• Olena H. Shvets,
• Vyacheslav E. Saraev,
• Svitlana V. Shishkina,
• Tetyana V. Shcherbakova and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2025, 21, 2021–2029, doi:10.3762/bjoc.21.157

• precipitation from non-polar solvents such as hexane and toluene did not lead to a complete separation of quinoxalinones 9 and Ph3PO. We attribute this to the ability of Ph3PO to form a strong hydrogen bond between the phosphoryl oxygen and a proton from the donor group of the second molecule [56][57][58], in

Photochemical reduction of acylimidazolium salts

• Michael Jakob,
• Nick Bechler,
• Hassan Abdelwahab,
• Fabian Weber,
• Janos Wasternack,
• Leonardo Kleebauer,
• Jan P. Götze and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2025, 21, 1973–1983, doi:10.3762/bjoc.21.153

• employed including carboxylic acids [37], xanthates [38], electron-rich toluene or heteroatom-substituted species [39][40][41][42], organoboron compounds [43][44] and organosilanes [43][45]. Moreover, three-component radical relay processes employing styrene derivatives have also been widely studied. In

Enantioselective desymmetrization strategy of prochiral 1,3-diols in natural product synthesis

• Lihua Wei,
• Rui Yang,
• Zhifeng Shi and
• Zhiqiang Ma

Beilstein J. Org. Chem. 2025, 21, 1932–1963, doi:10.3762/bjoc.21.151

• . Alcohol 28 was obtained from 27 in two steps, and was subsequently converted to hyperione A (30) and ent-hyperione B (31) by refluxing in toluene with Shvo’s catalyst 29. Notably, the authors found that hyperione A (30) could be obtained in higher yield and enantiopurity from alcohol 28 via a two-step

Synthesis of N-doped chiral macrocycles by regioselective palladium-catalyzed arylation

• Shuhai Qiu and
• Junzhi Liu

Beilstein J. Org. Chem. 2025, 21, 1917–1923, doi:10.3762/bjoc.21.149

• . Synthesis of N-doped macrocycles MC1, MC2, and MC3. Reaction conditions: a) Pd2(dba)3, Pt-Bu3·HBF4, NaOt-Bu, toluene, 110 °C, 24 h. 3a: 16%; 3b: 10%. b) Pd(OAc)2, PMe(t-Bu)2·HBF4, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), DMAc, microwave, 170 °C, 5 h. MC1: 5%; MC2: 90%; MC3: 85%. Supporting Information

Preparation of spirocyclic oxindoles by cyclisation of an oxime to a nitrone and dipolar cycloaddition

• Beth L. Ritchie,
• Alexandra Longcake and
• Iain Coldham

Beilstein J. Org. Chem. 2025, 21, 1890–1896, doi:10.3762/bjoc.21.146

• leaving group and activated, electron-poor dipolarophiles has been reported [31][32]. Treatment of aldehyde 4 with hydroxylamine in toluene at 60 °C for 1–3 h resulted in loss of the aldehyde as judged by 1H NMR spectroscopy of the crude mixture. When this was carried out in the presence of N

Systematic pore lipophilization to enhance the efficiency of an amine-based MOF catalyst in the solvent-free Knoevenagel reaction

• Pricilla Matseketsa,
• Margret Kumbirayi Ruwimbo Pagare and
• Tendai Gadzikwa

Beilstein J. Org. Chem. 2025, 21, 1854–1863, doi:10.3762/bjoc.21.144

• molecule, yielding BMN as the final product (Scheme 1B) [49]. In the initial trial, 12 mol % of the MOF catalyst was added to a vial containing benzaldehyde, malononitrile, toluene as solvent, and dodecane as internal standard, and the reaction was shaken at 50 °C. Aliquots were collected at 30 minutes

• increases the rate of the condensation reaction. Thus, we initially supposed that, though dodecane was only 5.6 vol % to toluene, its addition was decreasing the difference in lipophilicity between the MOF and the bulk solution, reducing the driving force to remove water from the MOF pores. When we compared

• reaction mixture. To address both concerns of performing the neat Knoevenagel reaction – product precipitation and the incomplete submersion of the MOF catalyst – we reduced the catalyst amount to 1.5 mol %. Surprisingly, the reaction conversions were higher than those in toluene with 12 mol % catalyst

Photoswitches beyond azobenzene: a beginner’s guide

• Michela Marcon,
• Christoph Haag and
• Burkhard König

Beilstein J. Org. Chem. 2025, 21, 1808–1853, doi:10.3762/bjoc.21.143

3,3'-Linked BINOL macrocycles: optimized synthesis of crown ethers featuring one or two BINOL units

• Somayyeh Kheirjou,
• Jan Riebe,
• Maike Thiele,
• Christoph Wölper and
• Jochen Niemeyer

Beilstein J. Org. Chem. 2025, 21, 1719–1729, doi:10.3762/bjoc.21.134

• ]. However, under the same coupling conditions (Pd2(dba)3, P(o-Tol)3, n-Bu4N+OH−, toluene/H2O, 90 °C), the reaction of diiodide 1 with bisboronic acids 75/6/7/8 gave only low yields of the desired macrocycles Me-M1 (7/32/22/21% for Me-M15/6/7/8). Thus, the macrocyclization via two-fold Suzuki coupling was

• routes towards macrocycles featuring one BINOL unit. a) Two-fold Suzuki coupling and b) two-fold Williamson synthesis. Reagents and conditions: i) bis(boronic ester) 75/6/7/8 (1.0. equiv), Pd2(dba)3 (0.1 equiv), P(o-Tol)3 (0.2 equiv), n-Bu4N+OH− (3.2. equiv), toluene/H2O 5:1, 90 °C; ii) ethylene glycol

• shown. Initially attempted route towards bis-BINOL macrocycles based on precursors Me-36 or Me-46. Conditions: i) 96 (2.2 equiv), Pd2(dba)3 (0.1 equiv), P(o-Tol)3 (0.2 equiv), n-Bu4N+OH− (3.2 equiv), toluene/H2O 5:1, 90 °C; ii) 96 (2.2. equiv), Cs2CO3 (3.0 equiv), CH3CN, 80 °C. Synthetic route towards

Continuous-flow-enabled intensification in nitration processes: a review of technological developments and practical applications over the past decade

• Feng Zhou,
• Chuansong Duanmu,
• Yanxing Li,
• Jin Li,
• Haiqing Xu,
• Pan Wang and
• Kai Zhu

Beilstein J. Org. Chem. 2025, 21, 1678–1699, doi:10.3762/bjoc.21.132

• nitration scale-up processes. HAZOP (hazard and operability study) also serves as a pivotal safety assessment methodology in continuous-flow nitration process development, leveraging its systematic framework for risk identification and process safety optimization. For instance, the nitration of toluene is

Synthesis of optically active folded cyclic dimers and trimers

• Ena Kumamoto,
• Kana Ogawa,
• Kazunori Okamoto and
• Yasuhiro Morisaki

Beilstein J. Org. Chem. 2025, 21, 1603–1612, doi:10.3762/bjoc.21.124

• diiodobenzene 5 using a Pd2(dba)3/PPh3/CuI catalytic system in toluene and Et3N under diluted conditions (monomer concentration = approximately 1.3 × 10−3 M) was performed. The corresponding cyclic dimer (Sp)-6 and trimer (Sp)-7 were detected mainly by thin-layer chromatography (TLC) and separated roughly using

• to be 0.65. Their PL of the cast films fabricated from the toluene solutions were also measured, and weak and inefficient luminescence were observed because of the aggregation-caused PL quenching. The PL lifetimes of (Sp)-6 and (Sp)-7 in the CHCl3 solutions were measured at each PL peak maximum; and

• '-dimethoxybiphenyl), PPh3, CuI, Bu4NF, MeOH, dehydrated THF, dehydrated toluene, and 1,4-diiodobenzene (5). Et3N was purchased and distilled over KOH. (Sp)-1 [31], (Rp)-1 [31], and 2 [48] were prepared as described in the literature. Synthesis of (Sp)-3 A mixture of (Sp)-1 (49.6 mg, 0.081 mmol), 2 (25.3 mg, 0.059

Thermodynamic equilibrium between locally excited and charge transfer states in perylene–phenothiazine dyads

• Issei Fukunaga,
• Shunsuke Kobashi,
• Yuki Nagai,
• Hiroki Horita,
• Hiromitsu Maeda and
• Yoichi Kobayashi

Beilstein J. Org. Chem. 2025, 21, 1577–1586, doi:10.3762/bjoc.21.121

• phenothiazine derivative, 12-phenyl-12H-benzo[a]phenothiazine, in toluene at room temperature has been estimated to be 28 ps (with an additional minor 0.7 ps component attributed to small-scale structural changes) [17]. It is also noted that the relaxation dynamics depend on the molecular structure and the

• surrounding environment. Considering that Pe–PTZ(TPA)2 is significantly larger than that in the aforementioned study, and that benzene has a slightly higher viscosity than toluene (0.60 and 0.56 cP at 297 K, respectively), the time constant of 2.43 ps of the first EAS (EAS1) can be attributed to

Azide–alkyne cycloaddition (click) reaction in biomass-derived solvent Cyrene^TM under one-pot conditions

• Zoltán Medgyesi and
• László T. Mika

Beilstein J. Org. Chem. 2025, 21, 1544–1551, doi:10.3762/bjoc.21.117

• used for click reactions such as chlorinated hydrocarbons [15][16], toluene [16], tetrahydrofuran (THF) [17][18], N,N-dimethylformamide (DMF) [19][20], N-methylpyrrolidone (NMP) [21], dimethyl sulfoxide (DMSO) [17][19][22], or acetonitrile [23] are classified into Class 1 and 2, of which applications

• capillary column (15 m × 0.25 mm × 0.25 µm) using H2 as a carrier gas. For the analysis, 10 μL of the reaction mixture was dissolved in 1 mL of ethyl acetate, followed by adding 10 μL toluene as the internal standard. Heating profile of GC–FID analysis: The initial temperature was 100 °C and was hold for

Ambident reactivity of enolizable 5-mercapto-1H-tetrazoles in trapping reactions with in situ-generated thiocarbonyl S-methanides derived from sterically crowded cycloaliphatic thioketones

• Grzegorz Mlostoń,
• Małgorzata Celeda,
• Marcin Palusiak,
• Heinz Heimgartner,
• Marta Denel-Bobrowska and
• Agnieszka B. Olejniczak

Beilstein J. Org. Chem. 2025, 21, 1508–1519, doi:10.3762/bjoc.21.113

• , trapping reactions (toluene, 60 °C) performed with 2d, functionalized with two spiro-cyclohexyl rings, and 5-mercaptotetrazoles 4a‒e led selectively to dithioacetals 10m‒q, which could be separated chromatographically as crystalline materials in good yields (46‒89%). Isomeric thioaminals of type 9 were not

• regioselectivity in high yields. Upon heating to 65 °C in toluene solution, in analogy to the well-known compounds 2a and 2b, they extruded N2 and the in situ-generated reactive thiocarbonyl S-methanides 1c and 1d, in absence of any trapping reagent, underwent 1,3-dipolar electrocyclization yielding the

• Table 1) in 1 mL of THF was heated at 45 °C (for 2a and 2b) or in 1 mL of toluene at 65 °C (for 2c and 2d). The evolution of nitrogen was controlled using a nitrometer (gas burette) connected with the reaction flask. In all cases the reaction was completed after ca. 3 h. After this time, the solvent was

Microwave-enhanced additive-free C–H amination of benzoxazoles catalysed by supported copper

• Andrei Paraschiv,
• Valentina Maruzzo,
• Filippo Pettazzi,
• Stefano Magliocco,
• Paolo Inaudi,
• Daria Brambilla,
• Gloria Berlier,
• Giancarlo Cravotto and
• Katia Martina

Beilstein J. Org. Chem. 2025, 21, 1462–1476, doi:10.3762/bjoc.21.108

• conditions already reported in the literature for aerobic protocols. As shown in Table 1, entries 1–3, we compared xylene, toluene, and acetonitrile as solvents. According to Bhanage and Wagh [13], Cu(II) catalyses the C–H amination in xylene at 140 °C for 14 hours under oxygen. We tested the reaction in

• refluxing toluene with 20 mol % of CuCl2 and observed a significantly decreased product yield (Table 1, entry 2). As Cao et al. [47] already have reported, acetonitrile improved the reaction efficiency, resulting in an increase in product yield to 78% when the reaction was performed at 80 °C. Interestingly

• of CuCl2 in toluene showed limited effectiveness, achieving 82% conversion but only a 28% yield of the final product. The remaining resulting mixture included 35% of the intermediate 2a-o and 19% of the hydrolysed product 2a-o-hydrol. However, the reaction performance in acetonitrile improved

Wittig reaction of cyclobisbiphenylenecarbonyl

• Taito Moribe,
• Junichiro Hirano,
• Hideaki Takano,
• Hiroshi Shinokubo and
• Norihito Fukui

Beilstein J. Org. Chem. 2025, 21, 1454–1461, doi:10.3762/bjoc.21.107

• slightly preferred at room temperature with approximately a 3:2 ratio of figure-eight and bathtub conformations. We have also estimated the activation barriers of the interconversion of 3 and 5 between the figure-eight and bathtub conformations by measuring VT 1H NMR spectra in toluene-d8 because the

Advances in nitrogen-containing helicenes: synthesis, chiroptical properties, and optoelectronic applications

• Meng Qiu,
• Jing Du,
• Nai-Te Yao,
• Xin-Yue Wang and
• Han-Yuan Gong

Beilstein J. Org. Chem. 2025, 21, 1422–1453, doi:10.3762/bjoc.21.106

• same group reported a stable push–pull [7]helicene diimide (compound 55) that exhibited notable chiroptical performance, with |gabs| and |glum| values of 1.12 × 10−2 and 5.0 × 10−3, respectively, in toluene [70]. Furthermore, compound 55 demonstrated solvent-dependent fluorescence and CPL behavior

• , and 60c – featuring 2,1,3-thiadiazole termini [75] (Table 20). Among them, compound 60c exhibited pronounced CPL activity in toluene (|glum| = 0.04, ΦF = 3%), demonstrating the efficacy of terminal heterocycle incorporation for boosting chiroptical performance. In 2024, Babu and co-workers developed

Tautomerism and switching in 7-hydroxy-8-(azophenyl)quinoline and similar compounds

• Lidia Zaharieva,
• Vera Deneva,
• Fadhil S. Kamounah,
• Nikolay Vassilev,
• Ivan Angelov,
• Michael Pittelkow and
• Liudmil Antonov

Beilstein J. Org. Chem. 2025, 21, 1404–1421, doi:10.3762/bjoc.21.105

• tautomer, which means that the switching would not be clean. According to relative energies and relative Gibb’s free energies, collected in Table 1, compound 1 should co-exist as a three component (E, KE and KK) tautomeric mixture in both toluene and acetonitrile. If the relative energies are taken into

• account in toluene E and KE are approximately equal as amount with a small presence (≈10%) of KK. The change of the solvent to acetonitrile does not change much the situation for the relatively equally polar E and KE, but leads to substantial stabilization of the more polar KK. The use of the relative

• molar fraction roughly between 60 and 70%). The relative energy between 3E and 3KE, given in Table 1, is 0.25 kcal/mol (60% E and 40% KE) in toluene, which very well corresponds to the experiment bearing in mind that toluene is slightly more polar and could stabilize the more polar KE tautomer. The

Oxetanes: formation, reactivity and total syntheses of natural products

• Peter Gabko,
• Martin Kalník and
• Maroš Bella

Beilstein J. Org. Chem. 2025, 21, 1324–1373, doi:10.3762/bjoc.21.101

• alcohols 13 and a binary Al/TBAB catalyst (Scheme 5) [40]. The reaction is carried out in toluene upon mild heating, providing the bicyclic products in high to excellent yields. Both electron-rich and electron-poor phenyls as well as aliphatic chains worked well, however, increased temperature and catalyst

A multicomponent reaction-initiated synthesis of imidazopyridine-fused isoquinolinones

• Ashutosh Nath,
• John Mark Awad and
• Wei Zhang

Beilstein J. Org. Chem. 2025, 21, 1161–1169, doi:10.3762/bjoc.21.92

• in 1,2-dichlorobenzene at 180 °C for 4 h, which gave 8a in 85% conversion and 82% isolated yield (Table 1, entry 3). Other solvents like toluene and xylene gave minimal or no product. Different combinations of temperature and reaction time couldn’t improve the yield. Among the various Lewis acids

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

• et al. for 5-position halogenated scaffolds [10]. Several different triazolopyrazine compounds bearing chlorine, bromine or iodine at the 5-position, gave no ipso-substituted (5-substituted) products when refluxed in toluene with phenethylamine, with all major products being substituted at the 8

• good yield with this straightforward methodology (and without the need for toluene reflux), and to determine the distribution of products obtained for this synthetic approach, by exhaustive analysis of reaction mixtures by HPLC, MS and NMR. Ultimately, 14 aminated derivatives of 5-chloro-3-(4

• column chromatography (and additionally by HPLC for the toluene reaction), the reactions also gave comparable yields of compound 2 (70% for toluene/silica and 82% for only phenethylamine at room temperature). Only the tele-substituted product was observed in either reaction mixture, consistent with