Recent applications of chiral calixarenes in asymmetric catalysis

• Mustafa Durmaz,
• Erkan Halay and
• Selahattin Bozkurt

Beilstein J. Org. Chem. 2018, 14, 1389–1412, doi:10.3762/bjoc.14.117

• of Boc group gave the target compounds 69. The catalytic activities of these prolinamide organocatalysts based on the calix[4]arene scaffold were evaluated for the model reaction between 21 and 70. The results showed that under solvent-free conditions at −25 °C, 2 mol % catalyst 69b with two

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

• either TrCl or DMTrCl, the products were recovered in 44% and 43% yields, respectively. Under solvent-free Corey conditions, rapid and chemoselective persilylation of ribonucleoside hydroxy functions was effected in a mixer ball mill (Scheme 2) [41]. Complete consumption of starting materials was

Phosphodiester models for cleavage of nucleic acids

• Satu Mikkola,
• Tuomas Lönnberg and
• Harri Lönnberg

Beilstein J. Org. Chem. 2018, 14, 803–837, doi:10.3762/bjoc.14.68

• other nucleophile, including solvent water or hydroxide ion, is able to compete. The large ribozymes have to provide a solvent-free environment that suppresses the nucleophilic attack of the vicinal 2´-OH by intrachain H-bonding and promotes the attack of an external nucleophile by appropriate

• preorganization, or the RNA chain is locked to a conformation where intrachain in-line attack is not possible. Several approaches have been developed to simulate these conditions with small molecular models. The solvent-free environment of the catalytic core of large ribozymes has been mimicked in small molecular

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

• . Currently, the Heck reaction is usually carried out by adding an excess of phase-transfer catalyst such as tetrabutylammonium bromide (TBAB) or tetrabutylammonium iodide (TBAI) to increase the reaction yield under both solvent-heating [19][20][21][22][23] and solvent-free conditions [24][25][26][27

• [33][34] and axitinib [35][36][37][38] (Scheme 1). Mechanochemistry as a burgeoning technique to promote solvent-free reactions has led to remarkable advances [39][40][41][42], particularly for cross-coupling reactions [43][44][45], involving Heck coupling with the aid of stoichiometric amounts of

• procedures [35][36], this mechanochemical protocol provided a solvent-free, highly efficient and tractable alternative, and the residual Pd content in the axitinib was determined to be no more than 2 ppm by ICP analysis. Conclusion In conclusion, a solvent-free, chemoselective Heck cross-coupling for the

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 reaction in comparison to completely solvent-free conditions. Finally, we observed that there was an effect of the dielectric constant of the solvent used in LAG on the stereochemistry of the product [27]. Although previously we were able to generate high yields of Wittig products under liquid

• the same rationale could be used in the case of our solvent-free conditions. In solution, ions are separated and stabilized by solvent molecules. Mechanistically we envision ions to start out as contact ion pairs, then solvent separated ion pairs (i.e., loose ion pairs) followed by free ion pairs

• . However, this pathway is shut down under solvent-free conditions, making everything in the system a contact ion pair. The traditional solution-based mechanism of the Wittig reaction proceeds via a four-membered oxaphosphetane intermediate. However, by incorporating the halide anion and the alkali metal

Mannich base-connected syntheses mediated by ortho-quinone methides

• Petra Barta,
• Ferenc Fülöp and
• István Szatmári

Beilstein J. Org. Chem. 2018, 14, 560–575, doi:10.3762/bjoc.14.43

• -assisted reactions, solvent-free conditions and the reusability of the catalyst (Table 1). Procedures are carried out as one-pot multicomponent transformations without the isolation of the intermediates formed. Therefore, with the application of nontoxic, readily available and inexpensive reagents, both

• , Samant et al. reported an ultrasound-promoted condensation catalysed by sulfamic acid [44]. As shown in Table 1, entries 39 and 40, both dichloroethane (DCE) and solvent-free conditions were tested. The catalyst worked at low temperature (28–30 °C) and the products were formed in short reaction times in

• -hydroxypropanals and cyclic secondary amines, Jha et al. achieved the synthesis of 2,2-dialkyl-3-dialkylamino-2,3-dihydro-1H-naphtho[2,1-b]pyrans under solvent-free conditions using pTSA as catalyst [75]. It is important to note, that during the reaction, 2,2-disubstituted 3-hydroxypropanals 26 decompose to

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

• ], 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

• products 3a and 4a were obtained in 73% and 77% yields, respectively (Scheme 4). Conclusion In summary, we have developed a solvent-free and efficient protocol to synthesize ortho-iodinated acetanilide derivatives with Pd(OAc)2 as the catalyst and N-iodosuccinimide as the halogen source under mechanical

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

• Ranjana Aggarwal and
• Suresh Kumar

Beilstein J. Org. Chem. 2018, 14, 203–242, doi:10.3762/bjoc.14.15

• acetic acid (Scheme 1). In the same report the other regioisomers 6-trifluoromethylpyrazolo[3,4-b]pyridines 20 were obtained under multicomponent solvent-free conditions by the reaction of hydrazine 14, β-ketonitrile 15 and β-diketone 17 as an exclusive product. The structures of both the regioisomers

• have been confirmed unambiguously by HMBC, HMQC and 19F NMR studies. The authors proposed that trifluoromethyl-β-diketone exists mainly in keto form 17 under solvent-free conditions whereas under solvent-mediated conditions the enolic form 21 towards the carbonyl carbon that carries the CF3 group is

• ). Interestingly, high yields of the corresponding pyrazolo[3,4-b]pyridines 34 were obtained when reactions were carried under solvent-free microwave irradiation. The synthesized pyrazolo[3,4-b]pyridines have shown potential cytotoxic activity against cervical HeLa and prostate DU 205 cancer cell lines. A similar

Binding abilities of polyaminocyclodextrins: polarimetric investigations and biological assays

• Marco Russo,
• Daniele La Corte,
• Annalisa Pisciotta,
• Serena Riela,
• Rosa Alduina and
• Paolo Lo Meo

Beilstein J. Org. Chem. 2017, 13, 2751–2763, doi:10.3762/bjoc.13.271

• further purification. The sodium alginate sample used (Sigma, lot 077K1583, extracted from Macrocystis pyrifera), presented an average content of mannuronic and guluronic units of 61% and 39%, respectively, and a molecular weight in the range 70–100 kDa. The AmCDs CD1–CD3 [37] were prepared by solvent

• -free aminolysis at 60 °C for 48 h of the heptakis(6-deoxy-6-iodo)-β-CD with a 140-fold mole-to-mole excess of the proper linear polyamine, i.e., 3-(N,N-dimethylamino)propylamine (A1) for CD1, bis(3-aminopropyl)methylamine (A2) for CD2 and bis-1,2-[(3-aminopropyl)amino]ethane (A3) for CD3. The products

A novel synthetic approach to hydroimidazo[1,5-b]pyridazines by the recyclization of itaconimides and HPLC–HRMS monitoring of the reaction pathway

• Dmitry Yu. Vandyshev,
• Khidmet S. Shikhaliev,
• Andrey Yu. Potapov,
• Michael Yu. Krysin,
• Fedor I. Zubkov and
• Lyudmila V. Sapronova

Beilstein J. Org. Chem. 2017, 13, 2561–2568, doi:10.3762/bjoc.13.252

• equivalent of C1-electrophile: R2COOH/T3P® [15], BrCN (R2 = NH2) [16], ArNCS/DCC (R2 = NHAr) [20]. Heterocyclization of 1-aminoimidazoles with 1,3-dicarbonyl or α,β-unsaturated carbonyl compounds (route B). Conditions: i) R1 = NH2, NHAlk, R2 = Ph, R3,4 = Alk, Ar, solvent-free [24], AcOH [25][26], R3 = Ph, R4

• = OEt, solvent-free [24]; ii) R1 = NH2, R2 = Ph, R3 = H, Me, R4 = Ar, ArCHO/MeOH/DMF [29] or R4 = H, HC(OEt)3/iPrOH [30]; iii) R1 = NH2, R2 = Ar, R3,4 = Alk, Ar, MeOH/N-methylmorpholine or DMF or AcOH [27][28], R3 = Ar, R4 = COOH, DMF [31], R3 = Ar, R4 = NMe2, AcOH/DMF [32]. Heterocyclization of 1

Exploring mechanochemistry to turn organic bio-relevant molecules into metal-organic frameworks: a short review

• Vânia André,
• Sílvia Quaresma,
• João Luís Ferreira da Silva and
• M. Teresa Duarte

Beilstein J. Org. Chem. 2017, 13, 2416–2427, doi:10.3762/bjoc.13.239

• field of supramolecular chemistry [27][28][29], for solvent-free preparation of co-crystals, and adducts [30][31][32][33][34][35][36][37][38], polymorphs [12], supramolecular aggregates [4][30][39][40][41][42], host–guest complexes [5][43][44][45], metal-organic frameworks (MOFs) [8][28][44][46][47][48

Mechanochemistry

• José G. Hernández

Beilstein J. Org. Chem. 2017, 13, 2372–2373, doi:10.3762/bjoc.13.234

• Jose G. Hernandez Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany 10.3762/bjoc.13.234 Keywords: green chemistry; mechanochemistry; organic chemistry; solvent-free; The scientific community’s general interest in using mechanical energy to trigger or

• of achieving chemical reactivity under solvent-free conditions. Additionally, the utilization of mechanochemical technology can often further simplify the posterior work-up procedures, having a deeper impact on the sustainability of the global synthetic process (reduction of waste, lower energy

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

• different copper species for the solvent-free mechanochemical CuAAC in a ball mill, we conducted a number of milling experiments where we assayed catalytic action of most commonly used copper(0), copper(I) and copper(II) catalysts. Mechanochemical reactions were compared to traditional solvent-based

• 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

• . 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