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

• . Subsequently, the mechanocoupling of hindered proline amino acid derivatives was developed to provide proline–proline dipeptides under solvent-free conditions. A deprotection–cyclization sequence yielded the corresponding diketopiperazines that were obtained with a high stereoselectivity which could be

• filtration of the catalytic system. 12 was engaged without further purification in a coupling reaction with Z-proline (5) and Boc-proline (6), in the solvent-free conditions described above. In both cases, the dipeptides 13 and 14 were obtained in good yields (78 and 61%, respectively). Deprotection followed

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

• impeller, and automated handling such as pumping and filtration. Since Lamaty and co-workers have shown in their seminal work that peptide synthesis could be performed in a ball-mill (BM) [9], various solvent-free or solvent-less peptide synthesis strategies have been developed [10][11][12][13][14][15][16

Main group mechanochemistry

• Agota A. Gečiauskaitė and
• Felipe García

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

• materials are becoming ever scarcer. A straightforward strategy to addressing the above is to simply remove or minimise solvent usage throughout any designated synthetic routes. One way to achieve a solvent-free, or nearly solvent-free, synthetic route is via the use of solid-state mechanochemical

• and/or reaction intermediates [16], which are not always attainable by solvent-free methods [17]. However, the benefits associated with solvent-free or nearly solvent-free synthetic routes are becoming increasingly difficult to deny [11][12][13], even in the eyes of the most sceptical synthetic

• susceptible to variable factors, both human and environmental [23]. In contrast, modern milling technologies address these issues through the use of enclosed solvent-free reaction environments and well-defined experimental conditions throughout the mechanochemical process [24][25]. Amongst the commercially

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

• solvent is the main component of the reaction system and, thus, the main source of waste in organic synthesis [35]. By far, performing the oxidation of alcohols under solvent-free conditions represents the best strategy to radically eliminate possible drawbacks in regard to waste disposal [36][37]. In

• amounts of the catalyst as well as molecular oxygen instead of air did not result in a significant improvement (Scheme 2, left side). To our great surprise, using Stahl’s catalyst, the mechanically activated oxidation of the model substrate 1a under solvent-free conditions proceed so quickly and

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

• .13.197 Abstract The mechanochemical Knoevenagel condensation of malononitrile with p-nitrobenzaldehyde was studied in situ using a tandem approach. X-ray diffraction and Raman spectroscopy were combined to yield time-resolved information on the milling process. Under solvent-free conditions, the reaction

• , chemistry, and pharmacy. Especially for organic syntheses, mechanochemistry is currently implemented as a green, fast, and efficient synthesis approach [1][2][3]. The syntheses are either solvent-free or require only a minimum amount of solvent. Consequently, solvation and desolvation phenomena can be

New bio-nanocomposites based on iron oxides and polysaccharides applied to oxidation and alkylation reactions

• Daily Rodríguez-Padrón,
• Alina M. Balu,
• Antonio A. Romero and
• Rafael Luque

Beilstein J. Org. Chem. 2017, 13, 1982–1993, doi:10.3762/bjoc.13.194

• most advantageous and environmentally friendly alternatives compared to the traditional routes [5][23]. This novel approach offers the possibility of a solvent-free process, avoiding environmental problems related to toxicity and the use thereof [24][25]. Moreover, the mechanochemical protocols have

• oxide–iron oxide–polysaccharide 4 (TiO2-Fe2O3-PS4) nanocomposites. The materials were successfully obtained using the proposed solvent-free methodology, which is depicted in Figure 1. The materials were characterized by the techniques presented below. The catalytic activity of these systems has been

Solvent-free and room temperature synthesis of 3-arylquinolines from different anilines and styrene oxide in the presence of Al₂O₃/MeSO₃H

• Hashem Sharghi,
• Mahdi Aberi,
• Mohsen Khataminejad and
• Pezhman Shiri

Beilstein J. Org. Chem. 2017, 13, 1977–1981, doi:10.3762/bjoc.13.193

• been developed in the presence of Al2O3/MeSO3H via one-pot reaction of anilines and styrene oxide. This methodology provides very rapid access to 3-arylquinolines in good to excellent yields under solvent-free conditions at room temperature in air. Keywords: 3-arylquinolines; Al2O3; MeSO3H; one-pot

• reaction; solvent-free conditions; Introduction Quinoline derivatives have received considerable interest because they are found in numerous natural products with many biological activities. They have also played an important role in medicinal chemistry due to their pharmacological properties [1][2][3][4

• styrene oxide at room temperature under solvent-free conditions (Scheme 1). Scheme 1 briefly compares the procedure reported by Wang and co-workers and our method. As it can be seen, the reaction can be performed under very short reaction time and low temperature. Results and Discussion To exploit

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

• present the development of mechanochemical procedures for PEG functionalization without the need for bulk solvents, offering a cleaner and more sustainable alternative to existing solution-based PEG procedures. The herein presented mechanochemical procedures enable rapid and solvent-free derivatization of

• pharmaceutical ingredients (APIs) is an emergent area that was recently reviewed [25]. In particular, solvent-free polymerization methods have been recently developed to access polyimines [26], polylactides [27], poly(phenylene vinylene) [28] and polyolefins [29]. There has been, however, limited effort towards

• -long solvent-based reaction conditions [19][40]. Our results also show that solvent-free conditions for the post-functionalization of native PEG is a good avenue to prevent chain lengthening, a known limitation of solvent-based techniques. Finally, our method is advantageous over solvent-based ones, as

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

• achieved by a different approach involving the homodimerization of 1-allyl- or 1-homoallylpyrroles by application of cross-metathesis chemistry. Keywords: diversity-oriented synthesis; mechanochemistry; multicomponent reactions; pyrroles; solvent-free synthesis; Introduction Symmetrical molecules formed

• disconnection employed and the structural diversity introduced at the three reaction components is summarized in Scheme 1. Our procedure involves the use of mechanochemistry, which deals with reactions promoted by mechanical energy and is emerging in recent years as a versatile tool that allows solvent-free

• additional hour. The reactions were routinely performed from 1 mmol of the starting materials, but two of them (leading to compounds 1a and 1n) were also carried out at a 10 mmol scale without any significant loss in yield. This solvent-free protocol combines the initial α-iodination of the starting ketone 4

Mechanochemical synthesis of small organic molecules

• Tapas Kumar Achar,
• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2017, 13, 1907–1931, doi:10.3762/bjoc.13.186

• (C–X), etc. is documented. Mechanochemical syntheses of heterocyclic rings, multicomponent reactions and organometallic molecules including their catalytic applications are also highlighted. Keywords: ball-milling; green chemistry; mechanochemistry; solid-phase synthesis; solvent-free synthesis

• been documented and thereby developing many existing protocols with superior results are further anticipated [8][9]. To address one of the major issues of green chemistry, i.e., minimizing chemical-waste/energy, solvent-free syntheses have become a popular research topic [8]. The mechanochemical

• techniques like ball-milling or hand grinding are considered to be promising candidates in solvent-free synthesis [10][11]. Mechanochemical methods deal with chemical transformations induced by mechanical energy, such as compression, shear, or friction [12]. Wilhelm Ostwald, a Russian-German chemist who

Solvent-free sonochemistry: Sonochemical organic synthesis in the absence of a liquid medium

• Deborah E. Crawford

Beilstein J. Org. Chem. 2017, 13, 1850–1856, doi:10.3762/bjoc.13.179

• . Keywords: mechanochemistry; organic; solvent-free; sonochemistry; synthesis; Introduction Mechanochemistry is typically regarded as the grinding of solid reagents in a ball mill (or mortar and pestle), to instigate and accelerate chemical reactions [1]. In recent years, mechanochemistry has evolved to

• of employing sonochemistry. Conclusion In conclusion, the first examples of ultrasound induced solvent-free condensation reactions are reported, forming a Schiff base 1 (which has significant applications in catalysis) and a 1,3-indandione 2. It was concluded that one of the key parameters in these

• reactions was the particle size of the starting materials, with a reduced particle size of <200 µm resulting in a homogeneous mixture leading to complete conversion to the product. This provides an excellent foundation for further investigations into solvent-free or solid-state sonochemistry, including

Mechanochemical synthesis of thioureas, ureas and guanidines

• Vjekoslav Štrukil

Beilstein J. Org. Chem. 2017, 13, 1828–1849, doi:10.3762/bjoc.13.178

• highlighted. While the literature is abundant on their preparation in conventional solution environment, it was not until the advent of solvent-free manual grinding using a mortar and pestle and automated ball milling that new synthetic opportunities have opened. The mechanochemical approach not only has

• and 1,2-phenylenediamine, benzimidazolidine-2-thiones 14a–c were isolated in 100% yields via cyclization of an unstable intermediate 13 (Scheme 3b,c). Compared to the solvent-free synthesis, the corresponding solution reactions resulted in lower yields (81–95%). Li and co-workers conducted a mortar

• were screened with electron-donating and electron-withdrawing groups attached to aromatic rings. The reactions were performed in a 1:1 stoichiometry by manual grinding in a mortar and by automated ball milling in a laboratory mixer mill. Also, the performance of solvent-free or neat grinding was

Selective enzymatic esterification of lignin model compounds in the ball mill

• Ulla Weißbach,
• Saumya Dabral,
• Laure Konnert,
• Carsten Bolm and
• José G. Hernández

Beilstein J. Org. Chem. 2017, 13, 1788–1795, doi:10.3762/bjoc.13.173

• diameter) [9], demonstrated to efficiently mediate the enzymatic kinetic resolution of secondary alcohols under solvent-free conditions in both mixer and planetary ball mills (Scheme 1b) [10]. Interestingly, this latter lipase (a commercial preparation known as Novozyme 345, hereinafter referred as CALB

Mechanochemical N-alkylation of imides

• Anamarija Briš,
• Mateja Đud and
• Davor Margetić

Beilstein J. Org. Chem. 2017, 13, 1745–1752, doi:10.3762/bjoc.13.169

• . Reactions under solvent-free conditions in a ball mill gave good yields and could be put in place of the classical solution conditions. The method is general and can be applied to various imides and alkyl halides. Phthalimides prepared under ball milling conditions were used in a mechanochemical Gabriel

• time, important progress was made in the development of various solvent-free organic reactions [5], especially by the use of the ball milling technique [6][7][8]. In continuation of our interest in eco-friendly organic syntheses [9][10][11][12][13][14], we studied mechanochemical N-alkylation reactions

• inevitable formation of 4, prevented clean mono-alkylation. The optimized reaction conditions were used to establish the scope of this reaction. Firstly, other alkyl halides were employed (Scheme 2). These experiments revealed that the solvent-free N-alkylation could be effectively carried out with different

An efficient Pd–NHC catalyst system in situ generated from Na₂PdCl₄ and PEG-functionalized imidazolium salts for Mizoroki–Heck reactions in water

• Nan Sun,
• Meng Chen,
• Liqun Jin,
• Wei Zhao,
• Baoxiang Hu,
• Zhenlu Shen and
• Xinquan Hu

Beilstein J. Org. Chem. 2017, 13, 1735–1744, doi:10.3762/bjoc.13.168

• -PEG1900-Im was heated with various organic bromides (2-(bromomethyl)pyridine, benzyl bromide and 1-(bromomethyl)naphthalene) to generate the corresponding imidazolium salts L1–L3 under solvent-free conditions. All imidazolium salts were water-soluble and air-stable. The resulted salts L1–L3 were

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, 1728–1734, doi:10.3762/bjoc.13.167

• applications on a large scale [45][46]. Very recently, Hernández, Frings, and Bolm developed a method to carry out the kinetic resolution of secondary alcohols through selective acylation using Candida antarctica lipase B, under solvent-free ball-milling conditions [47][48]. Inspired by this ground-breaking

• quite acceptable. On the other hand, no product was detected after the third cycle. To evaluate the denaturalization of the enzyme provoked by the milling process, a sample of fresh catalyst was milled for 1 h at 15 Hz under solvent-free conditions and in the presence of a LAG additive, finding that

• presents a slight decrease in ee compared with the resolution reaction using the milled enzyme under solvent-free conditions. This observation suggests that the LAG additive increases to some extent the degree of denaturation of the enzyme, reducing the enantiodiscrimination (ee = 91%) although maintaining

Oxidative dehydrogenation of C–C and C–N bonds: A convenient approach to access diverse (dihydro)heteroaromatic compounds

• Santanu Hati,
• Ulrike Holzgrabe and
• Subhabrata Sen

Beilstein J. Org. Chem. 2017, 13, 1670–1692, doi:10.3762/bjoc.13.162

• heating, ultrasonication and solvent-free conditions alleviated the drawbacks to a major extent [56][57][58][59][60][61]. One such useful strategy include manganese dioxide (MnO2)-mediated oxidative aromatization of 1,4-DHP 45 to afford substituted pyridine derivatives 46 under microwave conditions

Encaging palladium(0) in layered double hydroxide: A sustainable catalyst for solvent-free and ligand-free Heck reaction in a ball mill

• Wei Shi,
• Jingbo Yu,
• Zhijiang Jiang,
• Qiaoling Shao and
• Weike Su

Beilstein J. Org. Chem. 2017, 13, 1661–1668, doi:10.3762/bjoc.13.160

• easily recovered and reused for at least five times without significant loss of catalytic activity. Keywords: ball milling; Heck reaction; layer double hydroxides; solvent-free; supported Pd catalyst; Introduction High-speed ball milling (HSBM)-assisted transition metal-catalyzed cross-coupling reactions

• such as Heck, Suzuki, Sonogashira and Glaser reactions are still unusual methods for the formation of C–C bonds [1][2][3][4][5][6][7], but the method arouse considerable attention because of an environmentally benign and solvent-free synthesis approach as well as high efficiency and good atom economy

Phenylsilane as an effective desulfinylation reagent

• Wanda H. Midura,
• Aneta Rzewnicka and
• Jerzy A. Krysiak

Beilstein J. Org. Chem. 2017, 13, 1513–1517, doi:10.3762/bjoc.13.150

• silane procedure led to the single diastereomer 7a. In this case determination of the relative configuration as trans was based on a high coupling constant 3JP-H = 17.0 Hz, which evidenced retention of configuration during the desulfinylation process (Scheme 2). The reaction conducted under solvent-free

Mechanochemical borylation of aryldiazonium salts; merging light and ball milling

• José G. Hernández

Beilstein J. Org. Chem. 2017, 13, 1463–1469, doi:10.3762/bjoc.13.144

• spectroscopy. This time trace quantities of product 3a were detected (Table 1, entry 5). This interesting result under solvent-free conditions encouraged performing the light irradiation accompanied by milling to improve mixing and to increase the surface exposure of the reaction mixture. In a following set of

• direct formation of 3a [26][27]. This observation is in agreement with the findings by Jacobi von Wangelin et al., who described that upon irradiation of a solution of 1a in MeCN direct heterolytic cleavage of the aryldiazonium salt occurred [23][25]. However, the formation of 3a under solvent-free

Mechanochemistry-assisted synthesis of hierarchical porous carbons applied as supercapacitors

• Desirée Leistenschneider,
• Nicolas Jäckel,
• Felix Hippauf,
• Volker Presser and
• Lars Borchardt

Beilstein J. Org. Chem. 2017, 13, 1332–1341, doi:10.3762/bjoc.13.130

• Engineering, Saarland University, Saarbrücken, Germany Fraunhofer Institute for Material and Beam Technology IWS, Dresden, Germany 10.3762/bjoc.13.130 Abstract A solvent-free synthesis of hierarchical porous carbons is conducted by a facile and fast mechanochemical reaction in a ball mill. By means of a

• . Keywords: electrochemical energy storage; mesoporous; microporous; solvent-free; supercapacitor; templated carbon; Introduction Porous carbons are key components in many energy and environmentally-relevant applications, such as catalysis [1], gas storage and separation [2][3], and electrochemical energy

• ]. For example, the preparation of nanocarbon structures such as graphene sheets or fullerenes [39][40][41] as well as porous carbonaceous polymers [42][43] have been conducted mechanochemically. Our work demonstrates that a templating approach can be transferred into the solvent-free environment of a

Continuous-flow processes for the catalytic partial hydrogenation reaction of alkynes

• Carmen Moreno-Marrodan,
• Francesca Liguori and
• Pierluigi Barbaro

Beilstein J. Org. Chem. 2017, 13, 734–754, doi:10.3762/bjoc.13.73

• either using the Lindlar catalyst (84.6%) under smooth reaction conditions (298 K, 1 bar H2, Table 1, entry 1) or 16.2 wt % CeO2@TiO2 (97%), the latter resulting in a very high STY for 1a (18.86 kg L−1 h−1) under solvent-free conditions (Table 1, entry 2) [119]. Use of cerium oxide is certainly

Effect of the ortho-hydroxy group of salicylaldehyde in the A³ coupling reaction: A metal-catalyst-free synthesis of propargylamine

• Sujit Ghosh,
• Kinkar Biswas,
• Suchandra Bhattacharya,
• Pranab Ghosh and
• Basudeb Basu

Beilstein J. Org. Chem. 2017, 13, 552–557, doi:10.3762/bjoc.13.53

• achieved in the first two solvents (85–88%), the use of ethanol resulted in a low yield (47%). Thus the A3 coupling of salicylaldehyde, phenylacetylene and morpholine can be achieved under solvent-free conditions as well as in solvents like toluene or acetonitrile with the formation of the coupled product

• unusual but added role of the hydroxy group of salicylaldehyde, which paves the way to develop metal-free as well as solvent-free A3 coupling reactions leading to the formation of propargylamine – the useful synthetic intermediate and an important unit of many bio-active compounds. The reaction conditions

• only metal-catalyst-free approach from acetylene carboxylic acids that are difficultly accessible and with low atom economy. Thus the present reaction from easily available A3 components leading to the formation of propargylamine under metal-catalyst-free and solvent-free conditions could attract the

The synthesis of α-aryl-α-aminophosphonates and α-aryl-α-aminophosphine oxides by the microwave-assisted Pudovik reaction

• Erika Bálint,
• Ádám Tajti,
• Anna Ádám,
• István Csontos,
• Konstantin Karaghiosoff,
• Mátyás Czugler,
• Péter Ábrányi-Balogh and
• György Keglevich

Beilstein J. Org. Chem. 2017, 13, 76–86, doi:10.3762/bjoc.13.10

• and α-aryl-α-aminophosphine oxides was synthesized by the microwave-assisted solvent-free addition of dialkyl phosphites and diphenylphosphine oxide, respectively, to imines formed from benzaldehyde derivatives and primary amines. After optimization, the reactivity was mapped, and the fine mechanism

• ][34][35][36][37][38], while in a few cases the catalysts, i.e., PTSA [39], Na [40], TEA [21] or MoO2Cl2 [41], were used under solvent-free conditions. As for the microwave (MW)-assisted additions, only two cases were reported, but the catalytic variations were carried out in kitchen MW ovens [32][42

• ], and thus, do lack of exact temperatures, these results cannot be reproduced. From a ’green chemical’ point of view, the solvent-free and catalyst-free additions are of interest, however, in these reactions, relatively long reaction times (1.5–10 h), and/or unreasonably large excesses (50–150 equiv) of

Extrusion – back to the future: Using an established technique to reform automated chemical synthesis

• Deborah E. Crawford

Beilstein J. Org. Chem. 2017, 13, 65–75, doi:10.3762/bjoc.13.9

• organic compounds are highlighted. Extrusion is a well-established technique that has a vital role in the manufacturing processes of polymers, pharmaceuticals and food products. Furthermore, this technique has recently been applied to the solvent-free continuous synthesis of co-crystals and coordination

• extensive amount of research into continuous organic transformations by extrusion and encourage them to consider the potential that extrusion holds for continuous chemical synthesis, particularly under solvent-free conditions. Reactive extrusion (REX) Extrusion is employed most frequently in the polymer

• polymerisation reactions are typically dependent on the solvent employed, temperature and concentration [17], however, when they are conducted by extrusion, they are carried out under solvent-free conditions, which is a major advantage. It must also be noted that to carry out a reaction solvent-free, when a