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

• total time of four hours. After ball milling, an off-white powder was obtained which gave complex 5 in very good yield of 91% after extraction with CH2Cl2 and filtration. NMR analysis of 5 matched previously reported data [48][49] and showed no side products. It has to be mentioned that complex 5

• to the wide area of applications of mechanochemical synthesis but also showcase that transition metal complexes bearing additional functional groups can be prepared with a ball milling synthesis. We think that our protocol could be useful for the atom economic preparation of other complex catalysts

• complexes: Synthesis of bifunctional catalyst 5 via transmetallation. Mes = mesityl [48][49]. Application of bifunctional catalyst 5 in copper(I)-catalyzed hydrogenations: comparison of 5 prepared by solid state/ball milling (5bm) and liquid state (5ls) synthesis. Standard conditions: Substrate (0.40 mmol

Dissecting Mechanochemistry III

• Lars Borchardt and
• José G. Hernández

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

• 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

• ][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

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

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

• subjected to established the Zn/Cu mechanochemical conditions (Figure 3). The furan reaction under ball milling conditions led to a mixture of exo,exo- and exo,endo-cycloadducts 19 and 20 in a 0.8:1 ratio. This is in contrast to classical conditions with the Zn/Ag couple in THF, where the ratio is different

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

• reaction, we have performed the large-scale synthesis under the solvent-free (ball milling) conditions as shown in Figure 6. In this context, milling of the substrate (E)-N-(2-((4-bromobenzylidene)amino)phenyl)-4-methylbenzenesulfonamide (1c, 2.795 mmol) in the presence of 1.2 equiv of DDQ delivered 1.098

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

Application of the Meerwein reaction of 1,4-benzoquinone to a metal-free synthesis of benzofuropyridine analogues

• Rashmi Singh,
• Tomas Horsten,
• Rashmi Prakash,
• Swapan Dey and
• Wim Dehaen

Beilstein J. Org. Chem. 2021, 17, 977–982, doi:10.3762/bjoc.17.79

• nitrochromenobenzofuropyridine 21 was achieved after treatment of 16 with nitrostyrene in the presence of DABCO applying our previously reported ball milling procedure [40]. The synthesis of 22 was performed using the Perkin reaction [41]. The reaction of 16 with propionic anhydride and the corresponding sodium salt in the

Particle size effect in the mechanically assisted synthesis of β-cyclodextrin mesitylene sulfonate

• Stéphane Menuel,
• Sébastien Saitzek,
• Eric Monflier and
• Frédéric Hapiot

Beilstein J. Org. Chem. 2020, 16, 2598–2606, doi:10.3762/bjoc.16.211

• reactants throughout the solid mixture under ball-milling conditions. A weak association of bulky substrates and/or their corresponding products with the CD cavities under ball-milling conditions improved the mobility of the partners in the solid state. The reaction reactivity and selectivity were then

• constituting the reaction mixture on the reactivity for the synthesis of β-CDMts under ball-milling conditions. Additionally, in the presence of a base such as KOH, we show that the chemoselectivity of the reaction is significantly altered in favor of the β-CD product mono-substituted on the primary face, thus

• should be aware of the highly speculative nature of such interpretations because of the multiple processes (amorphization, particle comminution, product removal to form a fresh reactant surface) operating during ball-milling. Conclusion While the nature of the grinding processes is still not entirely

The B & B approach: Ball-milling conjugation of dextran with phenylboronic acid (PBA)-functionalized BODIPY

• Patrizia Andreozzi,
• Lorenza Tamberi,
• Elisamaria Tasca,
• Gina Elena Giacomazzo,
• Marta Martinez,
• Mirko Severi,
• Marco Marradi,
• Stefano Cicchi,
• Sergio Moya,
• Giacomo Biagiotti and
• Barbara Richichi

Beilstein J. Org. Chem. 2020, 16, 2272–2281, doi:10.3762/bjoc.16.188

• phenylboronic acid (PBA)-functionalized boron dipyrromethene (BODIPY) applying the ball milling approach. The ball milling formation of boron esters between PBA BODIPY and dextran proved to be more efficient in terms of reaction time, amount of reactants, and labelling degree compared to the corresponding

• biocompatibility while remaining fluorescent. Keywords: ball milling; boronic ester; dextran; bodipy; nanoparticles; Introduction In the last few decades, mechanochemistry has gathered a great deal of attention and a lot of efforts have been focused on its use in organic synthesis, catalysis, biotransformation

• evident with the development of atomized ball milling technologies, which allow for a better reproducibility and control of reaction parameters over traditional mortar or pestle [4][6]. Mechanochemical syntheses are not just a means for cleaner, safer, higher yielding, and more sustainable chemical

One-pot synthesis of isosorbide from cellulose or lignocellulosic biomass: a challenge?

• Isaline Bonnin,
• Raphaël Mereau,
• Thierry Tassaing and
• Karine De Oliveira Vigier

Beilstein J. Org. Chem. 2020, 16, 1713–1721, doi:10.3762/bjoc.16.143

• cellulose and a glucose content between 40.1% and 46.5%. The biomass feedstock was crushed by a simple ball milling procedure without further treatment. The one-pot conversion of Japanese cedar was carried out by combining Pt/C or Ru/C with 4 wt % of metal and Amberlyst 70 catalysts in a batch reactor of

Mechanochemical green synthesis of hyper-crosslinked cyclodextrin polymers

• Alberto Rubin Pedrazzo,
• Fabrizio Caldera,
• Marco Zanetti,
• Silvia Lucia Appleton,
• Nilesh Kumar Dhakar and
• Francesco Trotta

Beilstein J. Org. Chem. 2020, 16, 1554–1563, doi:10.3762/bjoc.16.127

• aprotic liquids (e.g., N,N-dimethylformamide or dimethyl sulfoxide), which affect the final result, especially for potential biomedical applications. This article describes a new, green synthetic pathway through mechanochemistry, in particular via ball milling and using 1,1-carbonyldiimidazole as the

• , and rhodamine B) and the still reactive imidazoyl carbonyl group of the NS. Keywords: β-cyclodextrin; ball-milling; crosslinking; green chemistry; mechanochemistry; nanosponges; Introduction The research in the fields of nanomedicine and nanotechnology has nowadays become predominant

• modifications of starch using ball milling have been reported. These included esterifications and etherifications of starch [19] and cellulose [20]. In 2017, Jicsinszky et al. obtained CD derivatives through a solid-state reaction, using a planetary ball mill [21][22] and by other green processes [23]. The main

Synthesis of 3-alkenylindoles through regioselective C–H alkenylation of indoles by a ruthenium nanocatalyst

• Abhijit Paul,
• Debnath Chatterjee,
• Srirupa Banerjee and
• Somnath Yadav

Beilstein J. Org. Chem. 2020, 16, 140–148, doi:10.3762/bjoc.16.16

• ]. Noël and co-workers reported the C3–H olefination of indoles using Pd(OAc)2 as a catalyst and molecular oxygen as the oxidant under continuous flow conditions [29]. Jia et al. reported the synthesis of 3-alkenylindoles using Pd(OAc)2 as the catalyst and MnO2 as the oxidant under ball milling conditions

Halide metathesis in overdrive: mechanochemical synthesis of a heterometallic group 1 allyl complex

• Ross F. Koby,
• Nicholas R. Rightmire,
• Nathan D. Schley,
• Timothy P. Hanusa and
• William W. Brennessel

Beilstein J. Org. Chem. 2019, 15, 1856–1863, doi:10.3762/bjoc.15.181

• ]∞, enable an otherwise unfavorable halide metathesis to proceed with mechanochemical assistance. From this result, we demonstrate that ball milling and unexpected solid-state effects can permit seemingly unfavored reactions to occur. Keywords: caesium; entropy; intermolecular forces; mechanochemistry

Metal-free mechanochemical oxidations in Ertalyte^® jars

• Andrea Porcheddu,
• Francesco Delogu,
• Lidia De Luca,
• Claudia Fattuoni and
• Evelina Colacino

Beilstein J. Org. Chem. 2019, 15, 1786–1794, doi:10.3762/bjoc.15.172

• on a mechanochemical activation [28]. In comparison to solution-based techniques, ball-milling procedures provide an ideal solution for overcoming many of the drawbacks described above, due to the simplicity of use, shorter reaction times, large-scale production, low cost and sustainability of this

• methodology [28][29][30][31][32][33][34][35][36][37][38][39]. In addition, impact forces, that are generated by ball-milling media involve a very minimal fraction of reactive material mimicking the ideal behavior/trend of highly diluted reactive systems. This peculiar aspect of mechanochemical reactions

• grinding mixture [51]. Two different mechanisms have been postulated for similar reactions in homogeneous phase: one occurs under acidic conditions, while the other works better in a basic medium through a cyclic dipolar mechanism (Scheme 2) [52][53]. On the contrary, under ball-milling conditions, it is