Reaction of oxiranes with cyclodextrins under high-energy ball-milling conditions

• László Jicsinszky,
• Federica Calsolaro,
• Katia Martina,
• Fabio Bucciol,
• Maela Manzoli and
• Giancarlo Cravotto

Beilstein J. Org. Chem. 2019, 15, 1448–1459, doi:10.3762/bjoc.15.145

• chemistry. The restricted mobility of solid-state components further reduces the aforementioned side-reactions and enhances the utilization in the CD substitution. Although many side reactions are suppressed in ball milling, they cannot be completely eliminated when alkaline hydroxides are used to activate

• practically constant at around room temperature (rt) during stirring. Freshly dried CDs were generally used in ball-milling reactions to minimise the hydrolysis of propylene oxide, but we also tested CD-hydrates. Unlike in the solution method, HEBM experiments provide for relatively poor opportunities to

• reaction between epoxides and CDs was successful. It was also found that reagent utilization was higher than in solution reactions and that oxirane hydrolysis in the presence of a strong base, NaOH, could be hampered under ball-milling conditions. Although the work-up and purification of the HEBM-reaction

Mechanochemical Friedel–Crafts acylations

• Mateja Đud,
• Anamarija Briš,
• Iva Jušinski,
• Davor Gracin and
• Davor Margetić

Beilstein J. Org. Chem. 2019, 15, 1313–1320, doi:10.3762/bjoc.15.130

• employment of different aromatic hydrocarbons in conjunction with anhydrides and acylation reagents. It was shown that certain FC-reactive aromatics could be effectively functionalized by FC acylations carried out under ball-milling conditions without the presence of a solvent. The reaction mechanism was

• studied by in situ Raman and ex situ IR spectroscopy. Keywords: ball milling; Friedel–Crafts reaction; mechanochemistry; Introduction The Friedel–Crafts reaction (FCR) is a very powerful tool in organic chemistry for the synthesis of aromatic ketones. It is of great industrial importance and widely used

• easily avoided by conducting the reaction in a closed vessel, by the aid of automated ball milling, which became a very effective synthetic method in recent time [13][14][15][16][17][18]. The first account on mechanochemical FC alkylation by Borchardt [19] demonstrates the utility of the mechanochemical

Understanding the unexpected effect of frequency on the kinetics of a covalent reaction under ball-milling conditions

• Ana M. Belenguer,
• Adam A. L. Michalchuk,
• Giulio I. Lampronti and
• Jeremy K. M. Sanders

Beilstein J. Org. Chem. 2019, 15, 1226–1235, doi:10.3762/bjoc.15.120

Mechanochemical amorphization of chitin: impact of apparatus material on performance and contamination

• Thomas Di Nardo and
• Audrey Moores

Beilstein J. Org. Chem. 2019, 15, 1217–1225, doi:10.3762/bjoc.15.119

• ball are strongly positively correlated with the obtained chitin amorphization. There is a deviation in kinetic energy at higher masses since the ball size decrease the internal milling path length. Study of chitin contamination by ball milling medium Chitin is an off-white yellow powder. Milling in

Unexpected polymorphism during a catalyzed mechanochemical Knoevenagel condensation

• Sebastian Haferkamp,
• Andrea Paul,
• Adam A. L. Michalchuk and
• Franziska Emmerling

Beilstein J. Org. Chem. 2019, 15, 1141–1148, doi:10.3762/bjoc.15.110

• monitoring multi-phase reactions during ball milling. Keywords: ball milling; C–C coupling; in situ; mechanochemistry; multivariate data analysis; Introduction Mechanochemistry offers a wide array of applications. It is used widely for synthesis of inorganic, metal-organic, and organic molecules and

Mechanochemical synthesis of poly(trimethylene carbonate)s: an example of rate acceleration

• Sora Park and
• Jeung Gon Kim

Beilstein J. Org. Chem. 2019, 15, 963–970, doi:10.3762/bjoc.15.93

• can now be obtained through green mechanochemical synthesis. In addition to the general merits of mechanochemistry, such as being solvent-free and resulting in high conversions, we herein explore rate acceleration under ball-milling conditions while the conventional solution-state synthesis suffer

• from low reactivity. The solvent-free mechanochemical polymerization of trimethylene carbonate using the organocatalysts 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) are examined herein. The polymerizations under ball-milling conditions exhibited significant

• rate enhancements compared to polymerizations in solution. A number of milling parameters were evaluated for the ball-milling polymerization. Temperature increases due to ball collisions and exothermic energy output did not affect the polymerization rate significantly and the initial mixing speed was

Mechanochemistry of supramolecules

• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2019, 15, 881–900, doi:10.3762/bjoc.15.86

• . Contrastingly, achieving syntheses through mechanochemical methods are generally time-saving, environmentally friendly and more economical. This review is written to shed some light on supramolecular chemistry and the synthesis of various supramolecules through mechanochemistry. Keywords: ball milling

• -workers (Figure 10). Under ball-milling conditions (20 Hz), the condensation of 4-formylphenylboronic acid, pentaerythritol and 1,3,5-tri(aminomethyl)-2,4,6-triethylbenzene afforded 94% of sphere-like compound 21 in 1 h [63]. In 2018, Wang and co-workers also demonstrated the synthesis of boronic ester

• -Bu2Si(OH)2, borasiloxane-based macrocycle 23 was obtained in >90% yield after 2 × 45 min of grinding [65]. In 2017, Xu and his group developed the first method towards the synthesis of 2-dimensional aromatic polyamides (2DAPAs) under solvent-free ball-milling conditions [66]. Reacting 1,3,5

Synthesis of acylglycerol derivatives by mechanochemistry

• Karen J. Ardila-Fierro,
• Andrij Pich,
• Marc Spehr,
• José G. Hernández and
• Carsten Bolm

Beilstein J. Org. Chem. 2019, 15, 811–817, doi:10.3762/bjoc.15.78

• , mechanosynthesis of lipids by ball milling techniques has remained essentially unexplored. In this work, a multistep synthetic route to access mono- and diacylglycerol derivatives by mechanochemistry has been realized, including the synthesis of diacylglycerol-coumarin conjugates. Keywords: ball mill; coumarin

• loads has led to mechanoenzymatic transformations [5][6][7], and to synthesize amino acid derivatives [8][9][10] and peptides [11][12][13] by ball milling and extrusion techniques. Similarly, mechanochemical derivatizations of sugars and sugar derivatives such as cyclodextrins (CDs) have proven

• compatible with the use of ball mills. These reports showed advantages such as higher selectivity by ball milling compared to classic solution methods and the possibility to effectively react CDs and reactants of different solubility profiles [14][15][16][17]. The compatibility of synthesizing biologically

Syntheses and chemical properties of β-nicotinamide riboside and its analogues and derivatives

• Mikhail V. Makarov and
• Marie E. Migaud

Beilstein J. Org. Chem. 2019, 15, 401–430, doi:10.3762/bjoc.15.36

• transformations without purification. The authors do not report ratios of α- and β-anomers or the yields, except for the pivaloyl derivative (77%) that was purified via silica gel chromatography. Mechanochemical methods (ball milling) of glycosylation of silylated nicotinamide 10a with 1 equivalent of 1,2,3,5

• presence of methanol under ball milling conditions (30 min at 25 Hz) resulted in the corresponding 1,4-dihydronicotinamide riboside NRH 21 isolated in quantitative yields. Alternatively, this deprotection procedure was conducted with 1 M sodium methoxide in MeOH over a longer period of time [58]. 1,4

Assembly of fully substituted triazolochromenes via a novel multicomponent reaction or mechanochemical synthesis

• Robby Vroemans,
• Yenthel Verhaegen,
• My Tran Thi Dieu and
• Wim Dehaen

Beilstein J. Org. Chem. 2018, 14, 2689–2697, doi:10.3762/bjoc.14.246

• was carried out for several salicylaldehydes and gave a clear improvement in the yield of the corresponding triazolochromenes and consequently showed to be a viable alternative for solid salicylaldehydes. Keywords: ball milling; multicomponent reaction; 3-nitro-2H-chromene; one-pot synthesis; 1,2,3

• furnish triazolochromenes in diminished yields in the one-pot three-component reaction (Figure 1, compounds 5c–f). Hence, a mechanochemical two-step protocol was developed, since a report by Jia and Zhang et al. [43] previously showed that ball milling could be a convenient manner to produce 3

• methodologies, the two highest yielding liquid salicylaldehydes in the one-pot protocol, i.e., 1a and 1b, were reacted in the two-step mechanochemically assisted reaction, giving rise to slightly lowered yields for compounds 5a and 5b. Hence, the use of the ball milling procedure is advantageous when solid

The mechanochemical synthesis of quinazolin-4(3H)-ones by controlling the reactivity of IBX

• Md Toufique Alam,
• Saikat Maiti and
• Prasenjit Mal

Beilstein J. Org. Chem. 2018, 14, 2396–2403, doi:10.3762/bjoc.14.216

• constructions [4][6]. Mechanochemical conditions such as ball milling are considered to be one of the premium techniques in solvent-free synthesis [7]. Under these conditions, maximum concentration is expected to put those systems under high stress and therefore violent exothermic reactions or even explosions

• benzaldehydes, aniline and IBX under ball-milling conditions an explosion was observed (Figure 1a; Caution! see experimental section) [30][31] and similar observations were made with Dess–Martin periodinane (DMP). On the other hand, benzamide was found to be unreactive with IBX and no reaction was observed

• quinazolin-4(3H)-ones (Figure 1d). In a recent report we have shown a successful dehydrogenative cross-coupling or CDC reaction using a combination of primary amines and phenyleneiodine diacetate (PIDA) under solvent-free ball-milling conditions, i.e., at the highest possible contact of the reactants [9

Mechanochemistry of nucleosides, nucleotides and related materials

• Olga Eguaogie,
• Joseph S. Vyle,
• Patrick F. Conlon,
• Manuela A. Gîlea and
• Yipei Liang

Beilstein J. Org. Chem. 2018, 14, 955–970, doi:10.3762/bjoc.14.81

• exploited grinding to facilitate disaggregation of DNA from tightly bound proteins through selective denaturation of the latter. Despite the wide application of ball milling to amino acid chemistry, there have been limited reports of mechanochemical transformations involving nucleoside or nucleotide

• contribution of mechanochemistry (and specifically, ball milling) to the isolation of biologically active materials derived from nuclei by grinding will also be outlined. Finally non-covalent associative processes involving nucleic acids and related materials using mechanochemistry will be described

• reaction [17]. In this review we have also adopted Hanusa’s formalism which distinguishes ball milling from other forms of mechanochemistry [18]. Perhaps most critical to the recent interest in this field has been the ability to deliver consistent and reproducible levels of mechanical energy using

Bromide-assisted chemoselective Heck reaction of 3-bromoindazoles under high-speed ball-milling conditions: synthesis of axitinib

• Jingbo Yu,
• Zikun Hong,
• Xinjie Yang,
• Yu Jiang,
• Zhijiang Jiang and
• Weike Su

Beilstein J. Org. Chem. 2018, 14, 786–795, doi:10.3762/bjoc.14.66

• highly efficient route for the synthesis of axitinib. Keywords: axitinib; ball-milling; dehalogenation; Heck reaction; indazoles; Introduction The palladium-catalyzed vinylation of alkenes in the presence of a base, known as the Heck reaction (Mizoroki–Heck reaction), is one of the most important

• TBAB [24][25][26][27]. However, for inert and liable to dehalogenation bromo-heteroarenes, no desired response had been obtained yet. Thus, this work was going to establish a mild and chemoselective olefination of 3-bromoindazoles under ball-milling conditions (Scheme 2). Results and Discussion

• excellent selectivity (trace of 4a) were achieved (Table S1, entry 12). In this way, the amount of TBAB could even be reduced to 5 mol % (Table S1, entry 14). Influence of grinding auxiliary In the process of ball milling, the grinding auxiliary was always found to be an efficient transfer medium between

Liquid-assisted grinding and ion pairing regulates percentage conversion and diastereoselectivity of the Wittig reaction under mechanochemical conditions

• Kendra Leahy Denlinger,
• Lianna Ortiz-Trankina,
• Preston Carr,
• Kingsley Benson,
• Daniel C. Waddell and
• James Mack

Beilstein J. Org. Chem. 2018, 14, 688–696, doi:10.3762/bjoc.14.57

• the Wittig reaction. Keywords: green chemistry; high-speed ball milling; HSBM; LAG; liquid-assisted grinding; Wittig; Introduction Mechanochemistry is maturing as a discipline and continuing to develop and grow [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Thus it is important to continue

Palladium-catalyzed ortho-halogenations of acetanilides with N-halosuccinimides via direct sp² C–H bond activation in ball mills

• Zi Liu,
• Hui Xu and
• Guan-Wu Wang

Beilstein J. Org. Chem. 2018, 14, 430–435, doi:10.3762/bjoc.14.31

• . China 10.3762/bjoc.14.31 Abstract A solvent-free palladium-catalyzed ortho-iodination of acetanilides using N-iodosuccinimide as the iodine source has been developed under ball-milling conditions. This present method avoids the use of hazardous organic solvents, high reaction temperature, and long

• corresponding N-halosuccinimides. Keywords: acetanilide; ball milling; C–H activation; halogenation; mechanochemistry; N-halosuccinimide; palladium catalysis; Introduction Aryl halides have been widely utilized in organic syntheses, which give access to a range of complex natural products [1][2]. However

• ], we have independently investigated the solvent-free ortho-iodination of acetanilides under ball-milling conditions [45]. In addition, the current reaction can be extended to ortho-bromination and ortho-chlorination by using the corresponding N-halosuccinimides. Herein, we report these regioselective

Solvent-free copper-catalyzed click chemistry for the synthesis of N-heterocyclic hybrids based on quinoline and 1,2,3-triazole

• Martina Tireli,
• Silvija Maračić,
• Stipe Lukin,
• Marina Juribašić Kulcsár,
• Dijana Žilić,
• Mario Cetina,
• Ivan Halasz,
• Silvana Raić-Malić and
• Krunoslav Užarević

Beilstein J. Org. Chem. 2017, 13, 2352–2363, doi:10.3762/bjoc.13.232

• development of medicinal chemistry and demands of the pharmaceutical industry for greener and more efficient approaches to chemical synthesis [23][24][25]. In accordance with the progress of mechanochemistry in organic syntheses [26], ball milling has been successfully implemented for solvent-free CuAAC

• solution, but these reactions are usually much slower [31]. Also, click polymerization was applied using a ball-milling process with no significant influence on the integrity of the polymer chain [27][32]. Herein we have studied the efficiency of copper catalysts with Cu(0), Cu(I) and Cu(II) oxidation

• procedures, CuAAC reactions proved to be more efficient under solvent-free ball-milling conditions, with ca. 15-fold increase in yields of products 5 and 8. Tested mechanochemical methods showed the same dependence of reactivity to the p-substituent as reactions in solution, H < Cl < Br < I, but the

A mechanochemical approach to access the proline–proline diketopiperazine framework

• Nicolas Pétry,
• Hafid Benakki,
• Eric Clot,
• Pascal Retailleau,
• Farhate Guenoun,
• Fatima Asserar,
• Chakib Sekkat,
• Thomas-Xavier Métro,
• Jean Martinez and
• Frédéric Lamaty

Beilstein J. Org. Chem. 2017, 13, 2169–2178, doi:10.3762/bjoc.13.217

• , France Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Saclay, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette, France 10.3762/bjoc.13.217 Abstract Ball milling was exploited to prepare a substituted proline building block by mechanochemical nucleophilic substitution

• and Discussion First we studied the preparation of simple Pro–Pro DKP as a model compound. The use of ball milling in peptide synthesis has drawn some attention in the recent years [20][21][22][23][24][25][26][27][28]. We took advantage of our extensive experience in peptide mechanosynthesis [20][23

• -3-(3-dimethylaminopropyl)carbodiimide (EDC), ethyl cyano(hydroxyimino)acetate (oxyma) in the presence of a base and a liquid additive, were adapted to the preparation of Z–Pro–Pro–OMe (7) and Boc–Pro–Pro–OMe (8, Table 1). It consisted in ball milling the two amino acid derivatives 5 or 6 with 2 in

The effect of milling frequency on a mechanochemical organic reaction monitored by in situ Raman spectroscopy

• Patrick A. Julien,
• Ivani Malvestiti and
• Tomislav Friščić

Beilstein J. Org. Chem. 2017, 13, 2160–2168, doi:10.3762/bjoc.13.216

• ] has rendered mechanochemical reactions by ball milling or grinding as viable, highly environmentally-friendly alternatives to solution-based chemistry. Importantly, mechanochemistry provides not only a means to conduct chemical transformations of poorly soluble reagents [17], but also enables access

• mechanochemical reactions. A significant recent advance in mechanistic studies of mechanochemical reaction mechanisms was the introduction of techniques for in situ, real-time monitoring of ball milling processes [27], first through synchrotron X-ray powder diffraction (XRPD) [28][29], and later by Raman

• molecular structure rather than its crystallinity, offering a powerful tool for in situ studies of mechanochemical organic reactions that often proceed through amorphous or eutectic intermediates. We now report a Raman spectroscopy study of the effect of ball milling frequency on the course of a model

Correction: Mechanochemical enzymatic resolution of N-benzylated-β³-amino esters

• Mario Pérez-Venegas,
• Gloria Reyes-Rangel,
• Adrián Neri,
• Jaime Escalante and
• Eusebio Juaristi

Beilstein J. Org. Chem. 2017, 13, 2128–2130, doi:10.3762/bjoc.13.210

• . Universidad 1001, Cuernavaca, Morelos, 62210, Mexico El Colegio Nacional, Luis Gonzáles Obregón 23, Centro Histórico, Ciudad de México, 06020, Mexico 10.3762/bjoc.13.210 Keywords: ball-milling; β3-amino acid; Candida antarctica lipase B; enzymatic resolution; mechanochemistry; The original published Tables

• under ball milling. Substrate scope for the enzymatic resolution of N-benzylated-β3-amino esters. Recycling capacity of immobilized CALB under HSBM conditions. Scaling-up of the enzymatic hydrolysis reaction under ball-milling using substrate rac-1a. Supporting Information Supporting Information File

Peptide synthesis: ball-milling, in solution, or on solid support, what is the best strategy?

• Ophélie Maurin,
• Pascal Verdié,
• Gilles Subra,
• Frédéric Lamaty,
• Jean Martinez and
• Thomas-Xavier Métro

Beilstein J. Org. Chem. 2017, 13, 2087–2093, doi:10.3762/bjoc.13.206

• Abstract While presenting particularly interesting advantages, peptide synthesis by ball-milling was never compared to the two traditional strategies, namely peptide syntheses in solution and on solid support (solid-phase peptide synthesis, SPPS). In this study, the challenging VVIA tetrapeptide was

• synthesized by ball-milling, in solution, and on solid support. The three strategies were then compared in terms of yield, purity, reaction time and environmental impact. The results obtained enabled to draw some strengths and weaknesses of each strategy, and to foresee what will have to be implemented to

• ][17]. While these approaches enable to circumvent the use of toxic solvents and bases [18][19][20], no comparison between ball-milling and conventional approaches was performed, discussed and communicated. Therefore, we performed this comparison by applying three different peptide synthesis strategies

Main group mechanochemistry

• Agota A. Gečiauskaitė and
• Felipe García

Beilstein J. Org. Chem. 2017, 13, 2068–2077, doi:10.3762/bjoc.13.204

• group compounds and frameworks. Keywords: ball milling; main group; mechanochemical synthesis; mechanochemistry; Introduction The original mainspring for the current expansion of solid state methodologies is the need for cleaner, safer and sustainable chemical transformations – particularly since raw

• chemist. Mechanochemistry is defined as the field of reactions caused by mechanochemical forces (e.g., compression, shear or friction) [18][19]. Examples of mechanochemical methods are manual and ball-milling grinding techniques [20][21][22]. Traditional manual mortar and pestle grinding methods are

• available ball milling designs [23][24], shaker and planetary mills are the most common mechanochemical apparatuses employed in synthetic laboratories [7][16][26][27]. The energy input may be adjusted by modifying parameters including milling time and frequency. Of equal importance in the reaction design is

Mechanically induced oxidation of alcohols to aldehydes and ketones in ambient air: Revisiting TEMPO-assisted oxidations

• Andrea Porcheddu,
• Evelina Colacino,
• Giancarlo Cravotto,
• Francesco Delogu and
• Lidia De Luca

Beilstein J. Org. Chem. 2017, 13, 2049–2055, doi:10.3762/bjoc.13.202

• primary and secondary alcohols to the corresponding aldehydes and ketones by mechanical processing under air. Ball milling was shown to promote the quantitative conversion of a broad set of alcohols into carbonyl compounds with no trace of an over-oxidation to carboxylic acids. The mechanochemical

• reaction exhibited higher yields and rates than the classical, homogeneous, TEMPO-based oxidation. Keywords: aldehydes; ball milling; ketones; mechanochemistry; oxidation reactions; TEMPO; Introduction Aldehydes and ketones constitute some of the most powerful and versatile building blocks that are

• aims to provide alternative methods to traditional syntheses in organic and inorganic chemistry [49][60][61]. Mechanochemistry is also used in supramolecular chemistry [62] and metal-organic chemistry [63]. In this work, we show that mechanical processing by ball milling can represent a viable solution

Mechanochemical Knoevenagel condensation investigated in situ

• Sebastian Haferkamp,
• Franziska Fischer,
• Werner Kraus and
• Franziska Emmerling

Beilstein J. Org. Chem. 2017, 13, 2010–2014, doi:10.3762/bjoc.13.197

• process both result in crystalline products suitable for single crystal X-ray diffraction. Keywords: ball milling; C–C coupling; in situ; Knoevenagel condensation; mechanochemistry; Introduction Mechanochemical syntheses have gained increasing popularity in different areas such as materials science

• ball milling is needed for the completion of the reaction. The ball mill was stopped after 36 minutes and the reaction in the closed jar was monitored with Raman spectroscopy. The data show that under these conditions the reaction to the final product is completed within two hours. Consequently

Solid-state mechanochemical ω-functionalization of poly(ethylene glycol)

• Michael Y. Malca,
• Pierre-Olivier Ferko,
• Tomislav Friščić and
• Audrey Moores

Beilstein J. Org. Chem. 2017, 13, 1963–1968, doi:10.3762/bjoc.13.191

• the functionalization of premade polymers. Recently, Yan and co-workers used ball milling to deacetylate chitin to afford chitosan [30]. We now provide a proof-of-principle demonstration of mechanochemical ω-functionalization of α-protected methoxy-PEG (mPEG) with –COOH, –OTs, –NH2, –Br, and –SH

• ball-milling. Namely, the tosyl moieties are known as excellent leaving groups, making tosylated mPEG (mPEGx–OTs) useful synthons for accessing further PEG derivatives. For this, we conducted a two-step one-pot reaction involving milling first the mPEG reactant with a base, followed by addition of p

• synthesis of other mPEG derivatives by mechanochemistry, through ball-milling reaction with additional nucleophiles. The synthesis of terminally brominated mPEG (mPEG–Br) derivatives was achieved by milling of mPEG–OTs with LiBr (Scheme 1b). Analysis of the milled reaction mixture by 1H NMR revealed the

High-speed vibration-milling-promoted synthesis of symmetrical frameworks containing two or three pyrrole units

• Marco Leonardi,
• Mercedes Villacampa and
• J. Carlos Menéndez

Beilstein J. Org. Chem. 2017, 13, 1957–1962, doi:10.3762/bjoc.13.190

• to give pyrrole derivatives 1. In some cases (compounds 1d, 1g, 1j, 1l, 1m, 1o), the ball milling-promoted iodination step failed and it was necessary to obtain the α-iodoketones 6 in a separate step by treatment of 4 with I2 and CuO in methanol. The iodination of 1-indanone (eventually leading to 1o