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

• -based nitrone with some maleimides via a mechanochemical route in a solvent-free medium [67][68]. The development of environmentally friendly green methodologies for the preparation of heterocyclic compounds via such cycloaddition reactions is a significant and ongoing research area that should not be

• viable candidates for use as solvents in the proposed reaction. Concurrently, the reaction was carried out in a solvent-free environment, and the product yields obtained in two distinct time periods are presented in Table 1 (entries 11 and 12). As can be deduced from these results, the reaction is found

• to be more sluggish in a solvent-free environment. Therefore, as evidenced in Table 1 (entries 8 and 9), methyl laurate is the most suitable solvent candidate for the reaction between nitrones and maleimides. Accordingly, methyl laurate, which facilitates the completion of this reaction in a

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

• irradiation was proven to be thermally, chemically and sunlight stable. The esterification of trans-3-(2-furyl)acrylic acid with ethanol, provided (1α,2α,3β,4β)-2,4-di(furan-2-yl)cyclobutane-1,3-dicarboxylic acid (CBDA-5) via a solvent-free [2 + 2] photodimerization from ethyl 2-furanacrylate and subsequent

• undergoes transacetalization with glycerol to produce a mixture of corresponding dioxane and dioxolane products (Scheme 60) [193]. Another strategy was proposed to synthesize potential aviation biofuels from furfural and 5,5-dimethyl 1,3-cyclohexanedione in water or under solvent-free conditions (Scheme 61

Solar thermal fuels: azobenzene as a cyclic photon–heat transduction platform

• Jie Yan,
• Shaodong Sun,
• Minghao Wang and
• Si Wu

Beilstein J. Org. Chem. 2025, 21, 2036–2047, doi:10.3762/bjoc.21.159

• azobenzene derivatives [82][83][84][85][86][87][88]. From an energy charging perspective, some solvent-free systems store energy in the solid state [89] or via photoinduced solid–liquid phase transitions [61][69][74], which occur because the melting temperature (Tm) of trans-azobenzene is above room

• azobenzene small molecules into polymer fibers [65], enabling solvent-free charging and discharging under visible light (Figure 6a). This material exhibited good capacity for releasing high-temperature heat (80–95 °C) at room temperature and in cold environments, along with an energy storage lifetime

• forward, improving the energy storage density of azobenzene-based solar thermal fuels remains an important research direction. However, significant opportunities exist for developing azobenzene derivatives that absorb visible light to NIR. In terms of charging and discharging methods, solvent-free systems

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

• intermediate depending on the lipophilicity of the pores. Under solvent-free conditions, we observed the formation of 2-(hydroxy(phenyl)methyl)malononitrile (HPMM, Figure 5), an intermediate which is subsequently dehydrated to yield the main product (BMN) as the reaction progresses [53]. Looking at the ratio

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 processes usually necessitate substantial solvent usage to ensure adequate thermal control and hazard mitigation. In contrast, flow-chemistry systems, leveraging their intrinsic process safety and enhanced mass/heat transfer efficiency, achieve solvent-free conditions in 45% of continuous-flow

High-pressure activation for the solvent- and catalyst-free syntheses of heterocycles, pharmaceuticals and esters

• Kelsey Plasse,
• Valerie Wright,
• Guoshu Xie,
• R. Bernadett Vlocskó,
• Alexander Lazarev and
• Béla Török

Beilstein J. Org. Chem. 2025, 21, 1374–1387, doi:10.3762/bjoc.21.102

• hydrostatic pressure (HHP) was found to be an efficient activation method in several catalyst- and solvent-free reactions and has found application for the syntheses of heterocycles and the preparation of active pharmaceutical ingredients (APIs) via acylation and acid- and solvent-free esterification. The

• reactions were carried out at ambient pressure (control) and under HHP (up to 3.8 kbar) conditions. These representative reactions provided higher yields for the products and HHP enabled truly green processes that are catalyst- and solvent-free, to occur with high yields and producing only non-toxic by

• ][33][34][35], especially in the realm of high pressure chemistry [36][37], in the present work we demonstrate a variety of new, catalyst- and additional solvent-free applications of HHP to develop green synthesis methods. Here, we describe several cyclization reactions for the preparation of a variety

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

• followed by the fluoride attack. Shibata and co-workers (2024) developed an amidation process by utilizing 1,1,2,2-tetrafluoroethyl-N,N-dimethylamine (TFEDMA) proceeding via an active acid fluoride in a mechanochemical fashion [49]. In this method, cinnamic acid was reacted with TFEDMA under solvent-free

• -acylbenzotriazole 97 via the Ni(II)-nitrene species 98 to afford its corresponding amide 47 in moderate yield (Scheme 30) [66]. Shimizu and co-workers (2019) reported a CeO2-catalyzed esterification of unactivated cinnamamide (99) and phenol in solvent-free conditions to afford the corresponding amide 24 in good

•  41B) [78]. Shankarling and co-workers (2020) directly prepared amide 12 from cinnamic acid (7) under solvent-free conditions catalyzed by graphene oxide via hydrogen-bonding activation (139) (Scheme 42A) [79]. The catalyst could be recycled multiple times without significant activity loss. Similarly

Biobased carbon dots as photoreductants – an investigation by using triarylsulfonium salts

• Valentina Benazzi,
• Arianna Bini,
• Ilaria Bertuol,
• Mariangela Novello,
• Federica Baldi,
• Matteo Hoch,
• Alvise Perosa and
• Stefano Protti

Beilstein J. Org. Chem. 2025, 21, 1024–1030, doi:10.3762/bjoc.21.84

• ; the first one involves the direct carbonization (at 200–400 °C) of the precursor material for 24–100 hours under solvent-free conditions. The obtained carbon nanomaterials exhibit predominantly a graphitic core structure. In contrast, under hydrothermal conditions, the starting substrates were

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

• dimeric molecules, instead of expected 9,10-(perfluoroalkyl)2ANTH [26]. To the best of our knowledge, perfluorobenzylation of anthracene has not been reported prior to this study. The only PAH perfluorobenzylations were reported by our group: with CORA using gas-phase solvent-free reactions in sealed

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

• crystal lattice and are often reversible, requiring either high-energy light or heat for initiation [6][7][8]. Notably, topochemical polymerizations align with the principles of green chemistry, as they are solvent-free and do not involve toxic reagents [9]. The highly ordered and uniform nature of

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

• enables solvent-free conditions for this transformation (Scheme 11B). Here, the aggregation state of the substrate and the reductant proved to be crucial to establish a fully operative protocol. The third reaction tested under mechanophotocatalytic conditions was the well-established decarboxylative

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

• . performed glycosylations under solvent-free conditions with poorly reactive disarmed per-O-acetylated (15) and per-O-benzoylated (18) glycosyl donors on being activated in air aided by catalytic amounts of a mild promoter, methanesulphonic acid (Scheme 3) [92]. The ester group was capable of conjugating

• phenol 16 and acceptor 19 to the anomeric position, thereby, making it suitable for glycoconjugate formation. They also reported the glycosylations leading to disaccharide 20 formation in solvent free conditions in significant 1,2-trans selectivity. This study holds the potential in improving the various

• glycosylation reactions making them solvent-free and being more environment friendly without compromising on the stereoselectivity. Thus, the acetyl and benzoyl group and similar derivatives are the most widely used protecting groups to obtain 1,2-trans glycosides in oligosaccharide syntheses. Ester groups in

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

• integrity over extended reaction times, even under high substrate concentrations and continuous flow conditions, achieving high turnover numbers of over 50000. This stability allowed for solvent-free reactions, significantly enhancing the sustainability of the process. Additionally, the authors have

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

• . The Mannich reaction with aromatic aldehydes and cyclic amines was performed efficiently on 2-naphthol, by using SiO2-supported copper triflate under solvent-free conditions, without an additional co-catalyst or additive (Scheme 3) [17]. The treatment of stoichiometric amounts of arylaldehydes

• the triple bond furnishes the furo-ring and the final oxidation affords the tricyclic product 22. Substituted quinolines 23 were obtained in a convenient solvent-free multicomponent reaction starting from electron-rich or electron-poor anilines, alkyl or arylaldehydes and terminal alkynes, performing

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

• Ritu Mamgain,
• Kokila Sakthivel and
• Fateh V. Singh

Beilstein J. Org. Chem. 2024, 20, 2891–2920, doi:10.3762/bjoc.20.243

• this Li and Jiang, created an effective ball-milling process for the N-arylation of amines 38 with the assistance of diaryliodonium salts 16 (Scheme 15) [67]. The arylation of an amino group or nitrogen heterocycle occurred effectively when the reaction is performed under solvent-free conditions or

Synthesis of pyrrole-fused dibenzoxazepine/dibenzothiazepine/triazolobenzodiazepine derivatives via isocyanide-based multicomponent reactions

• Marzieh Norouzi,
• Mohammad Taghi Nazeri,
• Ahmad Shaabani and
• Behrouz Notash

Beilstein J. Org. Chem. 2024, 20, 2870–2882, doi:10.3762/bjoc.20.241

• with 1,10-phenanthroline as cyclic imine under solvent-free conditions for the synthesis of pyrrole-fused phenanthroline. This reaction proceeds via in situ formation of zwitterion I through reaction of the aldehyde and malononitrile followed by 1,3-dipolar cycloaddition (Scheme 1a) [41]. Chen and co

• reaction was also attempted under solvent-free conditions at different temperatures (Table 1, entries 10–13). Interestingly, the highest yield of 70% of the desired product was achieved by conducting the reaction at 100 °C without using any solvent (Table 1, entry 12). After having identified the optimal

• isocyanides, gem-diactivated olefins, and cyclic imines (dibenzoxazepines, dibenzothiazepine, and triazolobenzodiazepine) under catalyst- and solvent-free conditions. Furthermore, the other advantages of this reaction include the manufacturing premium pharmaceutical scaffolds, a wide range of substrates

Mechanochemical difluoromethylations of ketones

• Jinbo Ke,
• Pit van Bonn and
• Carsten Bolm

Beilstein J. Org. Chem. 2024, 20, 2799–2805, doi:10.3762/bjoc.20.235

• efficiently converted to the target products under solvent-free conditions. The reactions proceed at room temperature and are complete within 90 minutes, demonstrating both efficiency and experimental simplicity. Keywords: ball milling; difluorocarbene; difluoromethylations; difluoromethyl enol ether

• compounds [35][36][37][38]. Notably, also sterically hindered alcohols, which are typically less reactive in solution, could be applied under solvent-free conditions in a ball mill [39], which was attributed to a better accessibility of the difluorocarbene in the mechanochemical environment [40]. Motivated

O,S,Se-containing Biginelli products based on cyclic β-ketosulfone and their postfunctionalization

• Kateryna V. Dil and
• Vitalii A. Palchykov

Beilstein J. Org. Chem. 2024, 20, 2143–2151, doi:10.3762/bjoc.20.184

• Biginelli synthesis of dihydropyrimidinones/thiones/selenones via acetic acid or solvent-free Yb(OTf)3-catalyzed tandem reaction of β-ketosulfone (dihydro-2H-thiopyran-3(4H)-one-1,1-dioxide), an appropriate urea, and arylaldehyde has been developed. The reaction proceeds with high chemo- and

• experimented with Lewis acids (Table 1, entries 10–12) to catalyze the reaction and observe low conversion with SrCl2. The reaction was significantly better with both La(NO2)3 and Yb(OTf)3 under solvent-free conditions (Table 1, entries 11 and 12, yield 61–65%). The most promising results were obtained by

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

• , it can be performed under solvent-free conditions [108] and is applicable to the synthesis of anellated pyrazoles [109]. In addition, arylsulfonate-substituted pyrazoles can be accessed using this protocol [110]. Due to their significance in pharmaceutical chemistry [11], the formation of

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

• afforded a heterogeneous nanoreactor that could be employed in acid-catalyzed transformations. The GBB reactions were performed with 1 mol % catalyst at 35 °C under solvent-free conditions. A synergistic catalytic effect between polyoxometalate and LDH was evidenced by a higher catalytic activity of the

• composite compared to the individual constituents tested separately. Solvent-free conditions afforded better yields than traditional solvents (water, toluene, DCM, EtOH, MeOH) and 12 adducts were synthetized in 84–96% yield. Finally, the catalyst was recycled six times with a slight decrease in efficiency

• that time, along with some 30 solvents. The most widely used conditions, however, remained those originally discovered by Groebke, Blackburn and Bienaymé, namely the use of Sc(OTf)3, perchloric acid or p-toluenesulfonic acid as catalysts, and methanol, ethanol or toluene as solvents, or under solvent

Synthetic applications of the Cannizzaro reaction

• Bhaskar Chatterjee,
• Dhananjoy Mondal and
• Smritilekha Bera

Beilstein J. Org. Chem. 2024, 20, 1376–1395, doi:10.3762/bjoc.20.120

• past several decades [19][20][21][22]. The base-mediated solvent-free Cannizzaro reaction was achieved through various methods, such as by grinding reactants in mechanochemical approaches and/or solid-supported bases. Minimizing the use of hazardous solvents not only reduces environmental impact but

• KSF clays as recyclable and heterogeneous catalysts to catalyze the Cannizzaro reaction by 1,4-diazabicyclo[2.2.2]octane under microwave irradiation and solvent-free conditions giving the products in excellent yields within seconds. The solid clay applied in the first cycle can be recovered and reused

• in subsequent reactions. Reddy and coworkers carried out the Cannizzaro reaction of aromatic aldehydes to the corresponding alcohols in high yields by crossed-Cannizzaro reactions employing solid-supported KF-Al2O3 as catalyst [26] under microwave irradiation using solvent-free conditions. The use of

Auxiliary strategy for the general and practical synthesis of diaryliodonium(III) salts with diverse organocarboxylate counterions

• Naoki Miyamoto,
• Daichi Koseki,
• Kohei Sumida,
• Elghareeb E. Elboray,
• Naoko Takenaga,
• Ravi Kumar and
• Toshifumi Dohi

Beilstein J. Org. Chem. 2024, 20, 1020–1028, doi:10.3762/bjoc.20.90

• increase in temperature facilitates the ligand coupling between the phenyl group and the carboxylate counterion. When heated at 140 °C for 2.5 h under solvent-free conditions, iodonium salt 7aa underwent carboxylate O-phenylation with complete phenyl group transfer, resulting in the formation of phenyl

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

Beilstein J. Org. Chem. 2024, 20, 787–814, doi:10.3762/bjoc.20.72

• ex-situ as demonstrated very recently by De Borggraeve and co-workers (Figure 5A) [67]. In a first chamber (A) HCl (gas) was prepared from NaCl and H2SO4 which then was directed towards a second chamber (B) which contains the alkene under solvent-free conditions. The scope of this reaction (Figure 5B

HPW-Catalyzed environmentally benign approach to imidazo[1,2-a]pyridines

• Luan A. Martinho and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2024, 20, 628–637, doi:10.3762/bjoc.20.55

• much greener as compared to methanol, it was chosen as the solvent to study the reaction scope. The use of water or solvent-free conditions resulted in much lower reaction yields (Table 1, entries 14–16). Next, the scope of the reaction was investigated with a range of 2-aminopyridines/2-aminothiazoles

Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles

• Periklis X. Kolagkis,
• Eirini M. Galathri and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2024, 20, 379–426, doi:10.3762/bjoc.20.36

• , lowering its LUMO energy, by withdrawing electron-density through a variety of covalent interactions. Green and sustainable approaches Solvent-free processes Alternative processes, that limit environmental pollution and toxic byproducts, came to the forefront of research for the introduction of novel

• and viability of these synthetic protocols, organic chemists have been opting towards the use of greener catalysts and solvents in drug development. Chemists dream to perform reactions under solvent-free conditions, which provide a greener approach towards organic transformations. Nowadays, the use of

• solvent-free reaction conditions has been introduced as a popular alternative to common organic solvents for many different organic transformations. The lack of an organic solvent can result in improved yields and reaction rates, more facile work-up processes and reduced waste, which are among the goals