New advances in asymmetric organocatalysis II

• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 766–769, doi:10.3762/bjoc.21.60

• ]. Kowalczyk and co-workers showed how asymmetric organocatalysis can benefit from mechanochemical activation. They established that Michael additions of thiomalonates to enones, catalyzed by cinchona-derived primary amines, is efficient and enantioselective under ball-milling conditions [24]. Kondratyev and

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

• manual grinding, vortex and shaker mixing, rod milling, and ball milling. By examining the advantages and limitations of each approach, we aim to provide an overview of the current state of synthetic photomechanochemistry to identify opportunities for future advancements in this rapidly evolving area of

• solvent. Mechanochemical synthesis, particularly through ball milling, has emerged as a powerful and sustainable technique that offers numerous advantages over traditional solution-phase methods [40][41][42]. By often eliminating the need for solvents, mechanochemistry reduces environmental impact and

• simplifies experimental procedures. Moreover, it often leads to shorter reaction times [43][44] and can overcome solubility limitations [45]. Similar to the effect of photons in light-mediated synthesis, mechanical forces generated during ball milling can induce unconventional reaction pathways [46] enabling

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

• efficiency and effectiveness as a synthetic approach. Furthermore, a transition-metal-free arylation of quinoxalines 17 and quinoxalinones 19 via aryl radicals was discussed by Li and co-workers in 2022. In this report the aryl radicals were generated by planetary ball milling of diaryliodonium salts 16 at a

• 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

• when a minimal quantity of water was used as a solvent in the presence of a base. The ball-milling method efficiently simplified the reaction process because, in contrast to typical solution methods, it may realize product formation without being affected by the solubility of the substrate and other

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

• absorption of mechanical energy and they are influenced by several factors, including the lack of solvation, changes in morphology and rheology of the reaction mixtures during the milling, and variations in concentration and dielectric environment. Consequently, an increased reactivity can be achieved

• , entry 1). The reaction was conducted in a PTFE milling equipment with two milling balls (diameter: 10 mm). Changing to a heavier milling ball (diameter: 15 mm) resulted in a yield of 67% of 3a (Table 1, entry 2). Stopping the reaction after 60 min gave product 3a in 72% yield (Table 1, entry 3). At a

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

• nucleophiles in this transformation. Keywords: asymmetric catalysis; iminium catalysis; mechanochemistry; organocatalysis; thioesters; Introduction Mechanochemistry, particularly solventless processes under ball milling conditions, offers the opportunity to devise unconventional reaction pathways [1][2][3][4

• studies by Bolm [12][13], and Juaristi et al. [14]. have significantly advanced chiral secondary amine-catalyzed stereoselective reactions under ball milling conditions, representing a widely explored activation mode in mechanochemical-mediated transformations. However, reports on chiral primary iminium

• -based catalytic system for the highly stereoselective addition of various bisthiomalonates to chalcones and dienones [29]. While recognizing the potential for greater selectivity enhancement and time savings with ball milling, hydrogen-bonding catalysis was effective only with aromatic enones, yielding

Synthesis of 2,2-difluoro-1,3-diketone and 2,2-difluoro-1,3-ketoester derivatives using fluorine gas

• Alexander S. Hampton,
• David R. W. Hodgson,
• Graham McDougald,
• Linhua Wang and
• Graham Sandford

Beilstein J. Org. Chem. 2024, 20, 460–469, doi:10.3762/bjoc.20.41

• , but the second fluorination step occurs only after reaction for several days. In the solid phase, mechanical milling of the diketone substrate with solid Selectfluor in the presence of sodium carbonate [13][14], and reaction of ketones with a strong base and an N–F reagent give rise to the

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

• development of greener synthetic technologies, like photocatalysis, organocatalysis, the use of nanocatalysts, microwave irradiation, ball milling, continuous flow, and many more. Thus, in this review, we summarize the medicinal properties of BIMs and the developed BIM synthetic protocols, utilizing the

• ]. In 2021, this methodology was reiterated by Wu et al., who conducted the reaction in the exact same conditions, utilizing the ball milling technique, instead of solid grinding, which slightly reduced reaction times and the catalyst loading necessary from 500 mg to 300 mg [119]. The substrate scope

Clauson–Kaas pyrrole synthesis using diverse catalysts: a transition from conventional to greener approach

• Dileep Kumar Singh and
• Rajesh Kumar

Beilstein J. Org. Chem. 2023, 19, 928–955, doi:10.3762/bjoc.19.71

• to reduce energy consumption and the carbon footprint. The traditional heating techniques used to synthesize compounds are being replaced by contemporary green alternative energy systems, such as photocatalysis, microwave irradiation, ultrasonic irradiation, grinding, and ball milling processes

Mechanochemical solid state synthesis of copper(I)/NHC complexes with K₃PO₄

• Ina Remy-Speckmann,
• Birte M. Zimmermann,
• Mahadeb Gorai,
• Martin Lerch and
• Johannes F. Teichert

Beilstein J. Org. Chem. 2023, 19, 440–447, doi:10.3762/bjoc.19.34

• milling the ligand precursor 1 with metallic copper powder in air [45]. Another mechanochemical pathway was published using K2CO3 as a base and copper(I) chloride [46][47]. This latter procedure is practical, avoids the use of solvents, and relies on an abundant and cheap base. We have recently disclosed

• during the milling process lead to agglutination of the remaining solids and therefore insufficient homogenization of the reaction mixture. This gave a mixture of compounds, in which the envisaged complex 5 could not be identified. A different approach was made using sodium hydride as a base (Table 1

• indicated the presence of 5, but also of unwanted side-products that could not be identified. Purification of 5 from this complex mixture turned out not to be feasible. Further modifications of the milling conditions did not lead to the elimination of these side-products, therefore the experiments with NaH

Dissecting Mechanochemistry III

• Lars Borchardt and
• José G. Hernández

Beilstein J. Org. Chem. 2022, 18, 1454–1456, doi:10.3762/bjoc.18.150

• , Colombia 10.3762/bjoc.18.150 In the past ten years, the use of mechanochemical techniques (e.g., grinding, milling, extrusion, pulsed ultrasonication, resonant acoustic mixing, etc.) have widespread in the field of organic chemistry, enabling the development of new and more sustainable protocols for

• Margetić used dibrominated polycyclic imides as substrates to generate reactive alkenes, which could be trapped in situ by several dienes through Diels−Alder cycloadditions by ball milling (Scheme 3) [7]. Further, Moores and co-workers synthesized phosphorus-bridged heptazine-based carbon nitrides (g-h-PCN

Mechanochemical synthesis of unsymmetrical salens for the preparation of Co–salen complexes and their evaluation as catalysts for the synthesis of α-aryloxy alcohols via asymmetric phenolic kinetic resolution of terminal epoxides

• Shengli Zuo,
• Shuxiang Zheng,
• Jianjun Liu and
• Ang Zuo

Beilstein J. Org. Chem. 2022, 18, 1416–1423, doi:10.3762/bjoc.18.147

• , University of Illinois at Chicago, Chicago, Illinois 60612, United States 10.3762/bjoc.18.147 Abstract In this paper, we report the mechanochemical synthesis of unsymmetrical salens using grinding and ball milling technologies, respectively, both of which were afforded in good yield. The chelating effect of

• monohydrochlorides and salicylaldehydes (blue in Scheme 2) took 1 hour for reaction completion. After adding another salicylaldehyde (red in Scheme 2), Et3N, and methanol, the second reaction step was completed in an additional hour, monitored by TLC. Yields of unsymmetrical salens using grinding and ball milling

• were summarized in Table 1. We were surprised that the overall yield from ball milling was lower than the overall yield from grinding, suggesting a higher revolution per minute (RPM) could be necessary to increase the reaction yield using ball milling. It is assumed that the forces are not equivalent

Polymer and small molecule mechanochemistry: closer than ever

• José G. Hernández

Beilstein J. Org. Chem. 2022, 18, 1225–1235, doi:10.3762/bjoc.18.128

• (mechanochemistry) can be accomplished through various experimental strategies. Among them, ultrasonication of polymeric matrices and ball milling of reaction partners have become the two leading approaches to carry out polymer and small molecule mechanochemistry, respectively. Often, the methodological differences

• molecule mechanochemistry sometimes overlap, evidencing the connection between both approaches. Keywords: ball milling; mechanochemistry; mechanophore; polymer; pulsed ultrasonication; Introduction In the past two decades, the growth in popularity of mechanochemistry has been unmistakable. During this

• (mechanophores) embedded along the polymer chains (Figure 1a) [1][2][3][4]. This is mostly accomplished through pulsed ultrasonication, and to a lesser extent by single-molecule force spectroscopy techniques [5][6]. The second approach habitually makes use of ball milling techniques to bring together small

From amines to (form)amides: a simple and successful mechanochemical approach

• Federico Casti,
• Rita Mocci and
• Andrea Porcheddu

Beilstein J. Org. Chem. 2022, 18, 1210–1216, doi:10.3762/bjoc.18.126

• ]. In general, mechanochemistry refers to studying solid-state chemical changes promoted by external mechanical energy, such as grinding or milling. A deeper understanding of its mechanistic aspects laid the basis for further growth in this topic, opening new routes to more efficient mechanochemical

• ][50][51][52][53][54], no systematic report of N-formylation and N-acetylation by ball milling has been reported yet. Here, we describe two complementary procedures to prepare formamides and acetamides, applied to primary and secondary aromatic and aliphatic amines. The methodologies directly involve

• HCO2H derivatives and CH3CO2H and two activating agents for promoting amide coupling. Results and Discussion We started our investigation by reacting p-methoxyaniline (1.0 mmol) with ammonium formate (3.0 mmol) (Table 1, entry 1) in a zirconia jar in the presence of one milling ball of the same material

Mechanochemical bottom-up synthesis of phosphorus-linked, heptazine-based carbon nitrides using sodium phosphide

• Blaine G. Fiss,
• Georgia Douglas,
• Michael Ferguson,
• Jorge Becerra,
• Jesus Valdez,
• Trong-On Do,
• Tomislav Friščić and
• Audrey Moores

Beilstein J. Org. Chem. 2022, 18, 1203–1209, doi:10.3762/bjoc.18.125

• functional theory (DFT) and electron energy loss spectroscopy (EELS). Compared to traditional furnace-based techniques, the presented method utilizes milder conditions, as well as shorter reaction times. Both samples of g-h-PCN directly after milling and aging and after an hour of annealing at 300 °C (g-h

• broad Bragg reflections at 2θ = 16° and 28°. This suggests a high thermal stability of the g-h-PCN structure, being formed during the mild milling and aging conditions, with no need for annealing. X-ray photoelectron spectroscopy (XPS) To gain insight into the atomic speciation within the structure and

• well as a peak centered on 292.1 eV due to charging effects [39]. The presence of C=N bonds established by XPS indicates that the heptazine structure was preserved during milling and aging with Na3P. Nitrogen 1s focused scans of g-h-PCN showed a 62% to 38% ratio of pyridinic to pyridonic-N type

Derivatives of benzo-1,4-thiazine-3-carboxylic acid and the corresponding amino acid conjugates

• Péter Kisszékelyi,
• Tibor Peňaška,
• Klára Stankovianska,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2022, 18, 1195–1202, doi:10.3762/bjoc.18.124

• . Several attempts were made to combine the benzothiazine motif with amino acid methyl esters (Scheme 4) using coupling agents (EDC, COMU, T3P®, etc.) or through acid chloride (SOCl2 and (COCl)2) in a flask with stirring or under ball-milling conditions. However, we were unable to isolate the desired amides

Automated grindstone chemistry: a simple and facile way for PEG-assisted stoichiometry-controlled halogenation of phenols and anilines using N-halosuccinimides

• Dharmendra Das,
• Akhil A. Bhosle,
• Amrita Chatterjee and
• Mainak Banerjee

Beilstein J. Org. Chem. 2022, 18, 999–1008, doi:10.3762/bjoc.18.100

• mechanical grinding or milling, has garnered massive interest among chemists owing to its green attributes like solvent-free, clean, atom economic, and time-efficient, and has been identified by the IUPAC as one of 10 world-changing technologies [47]. While milling has received more focus, the simpler form

• requires the use of a solid acid catalyst [52], apart from the use of high-cost, high-end milling equipment which limits to laboratory scale only. Therefore, developing an operationally simple, environmentally benign protocol, potentially useful for the batch-scale synthesis of aryl halides is highly

• of the solid acid catalyst and the cost of high-end milling instruments are additional considerations for that method [52]. Conclusion In conclusion, we have developed a facile and sustainable mechanochemical route for the catalyst-free halogenation of phenol and aniline derivatives using N

Palladium-catalyzed solid-state borylation of aryl halides using mechanochemistry

• Koji Kubota,
• Emiru Baba,
• Tamae Seo,
• Tatsuo Ishiyama and
• Hajime Ito

Beilstein J. Org. Chem. 2022, 18, 855–862, doi:10.3762/bjoc.18.86

• , Japan 10.3762/bjoc.18.86 Abstract This study describes the solid-state palladium-catalyzed cross-coupling between aryl halides and bis(pinacolato)diboron using ball milling. The reactions were completed within 10 min for most aryl halides to afford a variety of synthetically useful arylboronates in

• , mechanochemical synthesis using ball milling has attracted considerable attention as an efficient solvent-free synthetic technique [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. Notably, the strong mechanical agitation provided by ball milling enables efficient solid-state organic

• ). The reactions were conducted in a Retch MM400 ball mill in a stainless-steel milling jar (1.5 mL) at 30 Hz using one stainless-steel ball (diameter: 5 mm) for 10 min. We used a commercially available temperature-controllable heat gun that was placed directly above the ball-milling jar to control the

Complementarity of solution and solid state mechanochemical reaction conditions demonstrated by 1,2-debromination of tricyclic imides

• Petar Štrbac and
• Davor Margetić

Beilstein J. Org. Chem. 2022, 18, 746–753, doi:10.3762/bjoc.18.75

• was replaced by the Zn/Cu couple which was prepared without any metal activation by in situ ball milling of zinc and copper dusts. The advantage of the ball milling process is that the whole procedure is operationally very simplified. The reactive alkene generated was trapped in situ by several dienes

• and the respective Diels−Alder cycloadducts were obtained. It was demonstrated that mechanochemical milling offers complementary conditions to solution (thermal) reaction by allowing chemical transformations to proceed which were not possible in solution and vice versa. Keywords: ball milling

• usual procedure from Zn and silver acetate. Several simplifications of the Zn/Ag couple preparation were tested and showed that simple milling with Zn dust and Ag dust or wire can be also applied (Table 1, entries 5–8) [21]. Further improvement in the procedure was the replacement of the Ag dust with Cu

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• in the fixed-bed material that interact with the oscillating electromagnetic field. Recently, Rebrov and co-workers disclosed the direct amide formation of a carboxylic acid and anilline using high energy ball milling to prepare the sulfated TiO2 (50 wt %)/NiFe2O4 (50 wt %) catalyst that serves as

Mechanochemical halogenation of unsymmetrically substituted azobenzenes

• Dajana Barišić,
• Mario Pajić,
• Ivan Halasz,
• Darko Babić and
• Manda Ćurić

Beilstein J. Org. Chem. 2022, 18, 680–687, doi:10.3762/bjoc.18.69

• application of solid-state methods [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46], particularly ball milling [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46], which has proven to be an environmentally friendly and powerful

• alternative to conventional solvent-based protocols, offering unique advantages in terms of sustainability, reaction times, yields, reactant solubility, selectivity, and chemical reactivity. Although ball milling methods are widely used for the synthesis of various classes of compounds [26][27][28][29][30][31

• -halosuccinimide (NXS, X = Br, I) as halogen source [47]. Two years later in 2017, Eslami's group applied a ball-milling method to synthesize aryl bromides and α-bromoketones with N-bromosuccinimide (NBS) and MCM-41-SO3H catalyst and no liquid additives [48]. In 2018, Wang and co-workers developed the ball-milling

DDQ in mechanochemical C–N coupling reactions

• Shyamal Kanti Bera,
• Rosalin Bhanja and
• Prasenjit Mal

Beilstein J. Org. Chem. 2022, 18, 639–646, doi:10.3762/bjoc.18.64

• -Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is a commonly known oxidant. Herein, we report that DDQ can be used to synthesize 1,2-disubstituted benzimidazoles and quinazolin-4(3H)-ones via the intra- and intermolecular C–N coupling reaction under solvent-free mechanochemical (ball milling) conditions. In

• toward the synthesis of 1,2-disubstituted benzimidazoles [39] under mechanochemical (ball milling) conditions (Figure 1a). In addition, the one-pot coupling of 2-aminobenzamides with aryl/alkyl aldehydes in the presence of DDQ resulted in substituted quinazolin-4(3H)-one [40] derivatives (Figure 1b

• operating milling frequency from 21 to 16 Hz (Supporting Information File 1, Table S1, entry 9). On the other hand, the yield of product 5a was unaffected by increasing the operating frequency from 21 Hz to 25 Hz (Supporting Information File 1, Table S1, entry 8). 1,2-Disubstituted benzimidazoles are

Menadione: a platform and a target to valuable compounds synthesis

• Acácio S. de Souza,
• Ruan Carlos B. Ribeiro,
• Dora C. S. Costa,
• Fernanda P. Pauli,
• David R. Pinho,
• Matheus G. de Moraes,
• Fernando de C. da Silva,
• Luana da S. M. Forezi and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 381–419, doi:10.3762/bjoc.18.43

Multi-faceted reactivity of N-fluorobenzenesulfonimide (NFSI) under mechanochemical conditions: fluorination, fluorodemethylation, sulfonylation, and amidation reactions

• José G. Hernández,
• Karen J. Ardila-Fierro,
• Dajana Barišić and
• Hervé Geneste

Beilstein J. Org. Chem. 2022, 18, 182–189, doi:10.3762/bjoc.18.20

• techniques, in this work we studied the reactivity of N-fluorobenzenesulfonimide (NFSI) by ball milling. We corroborated that, by mechanochemistry, NFSI can engage in a variety of reactions such as fluorinations, fluorodemethylations, sulfonylations, and amidations. In comparison to the protocols reported in

• ; sulfonylation; Introduction Mechanosynthesis of organic molecules and materials using mechanochemical techniques such as ball milling, extrusion, grinding, etc. [1][2][3] have enabled the development of known and new chemical transformations in a more sustainable fashion [4]. Commonly, mechanochemical

• reactions by ball milling involve the mechanical treatment of at least one solid reagent in the presence of other solid, liquid or gaseous reaction partners or additives [5][6]. Due to the particular reaction conditions in which mechanochemical reactions by milling are carried out, reagents need to exhibit

N-Sulfinylpyrrolidine-containing ureas and thioureas as bifunctional organocatalysts

• Viera Poláčková,
• Dominika Krištofíková,
• Boglárka Némethová,
• Renata Górová,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2021, 17, 2629–2641, doi:10.3762/bjoc.17.176

• influence on the catalytic reactions. Under ball-milling conditions, the Michael adducts were obtained in good yields but with slightly lower enantiomeric purities than in solution. DFT calculations elucidated its mode of action and confirmed a dual activation mode, which combines enamine activation of

• organocatalytic transformations were successfully performed under solvent-free ball-milling conditions [30][31]. In this context, we describe the synthesis of new pyrrolidine appended sulfinylurea and thiourea organocatalysts and their assessment in Michael additions of aldehydes to nitroalkenes. Furthermore, we

• )benzene (7b). Hexanal (6b) reacted successfully with 4-fluoro-β-nitrostyrene (7c) and gave product 8d under all conditions tested (in solution, solvent-free, and ball-milling conditions, vide infra). Again, small amounts of catalyst (S,R)-C2 gave the best chemical yield. Catalyst (S,R)-C2 (3 mol %) in

A straightforward conversion of 1,4-quinones into polycyclic pyrazoles via [3 + 2]-cycloaddition with fluorinated nitrile imines

• Greta Utecht-Jarzyńska,
• Karolina Nagła,
• Grzegorz Mlostoń,
• Heinz Heimgartner,
• Marcin Palusiak and
• Marcin Jasiński

Beilstein J. Org. Chem. 2021, 17, 1509–1517, doi:10.3762/bjoc.17.108

• inorganic bases, such as Et3N, K2CO3, and DBU. Along with the “traditional” reaction performed in solution, a mechanochemical approach using ball milling was also tested. The obtained results are collected and compared in Table 1. They show that the best results were achieved using dry THF as a solvent and