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

• of their low reactivity. Recently, Li and Su with co-workers have developed a liquid-assisted grinding (LAG) method for the Suzuki–Miyaura coupling between aryl chlorides and boronic acids to synthesize the biaryls in nearly quantitative yield. Under optimized conditions 2 mol % Pd(OAc)2 and 4 mol

• acetic acid (LAG). Contrastingly, when acrylic esters were treated with 8 mol % of PdCl2 and in absence of acetic acid, β,β-diindolylpropionates were obtained as the major product (Scheme 14) [70]. C–N bond synthesis Amongst C–N bonds the amide bonds are most abundant and important too [71]. According to

• selectfluor [101][102]. They could control the selectivity of the reaction through LAG using ACN (≈10% v/v of total materials) to get predominantly mono-fluorinated product over difluorinated derivatives (Scheme 27). Contrastingly, addition of 1.0 equiv of Na2CO3 led to switching of the selectivity

Mechanochemical synthesis of thioureas, ureas and guanidines

• Vjekoslav Štrukil

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

• phase to a mixture treated by manual grinding or ball milling [19]. What was in the beginning termed as "solvent-drop grinding" (SDG) eventually became "liquid-assisted grinding" or LAG, now a well-established method for improving the outcome of mechanochemical reactions [20]. In continuation of this

• research, Friščić et al. introduced the so called "ion and liquid-assisted grinding" or ILAG by recognizing the effect of cations such as Na+, K+ or NH4+ or anions like Cl−, NO3− and SO42− on the formation of polymorphs during LAG synthesis of metal-organic frameworks [21]. Recently, Jones et al. employed

• polymeric macromolecular catalysts, e.g., PEG 200 and PEG 10000 as solid auxiliaries to enhance crystallization under LAG mechanochemical conditions in "polymer and liquid-assisted grinding" or POLAG [22][23]. While the focus in these investigations has been on the improvement of the macroscopic parameters

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

• addition of a small amount of solvent for LAG (liquid-assisted grinding) [27] was tested as well. The results are collected in Table 1. The best results were achieved by the use of K2CO3 as base, with large excess of dibromide and carbonate. Within one hour of milling, 1 was quantitatively converted to the

• comparison with the synthesis carried out in solution (acetone, 60 °C) showed a significant reduction in time (Table 1, entry 11). Also less efficient was the use of acetone under LAG conditions (Table 1, entry 9). It was found that the outcome of the reaction could be efficiently controlled by variation of

• alkyl halides, however, the conditions had to be optimized for each substrate. In particular, reactions carried out by a one-pot, two-step process [28] of 1 with K2CO3 (producing in situ the potassium imide salt), followed by the addition of the halide and further milling in conjunction with LAG (DMF

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

• . Several chiral organocatalysts and even enzymes have proved to be resistant to milling conditions, which allows for rather efficient enantioselective transformations under ball-milling conditions. The present article reports the first example of a liquid-assisted grinding (LAG) mechanochemical enzymatic

• ][40][41][42][43][44], so this converts mechanochemistry into a green technique, whose field of application is still very wide. In this context, the use of a minimal amount of solvent (LAG) enable the development of convenient ball-milling protocols. In particular, LAG facilitates mechanochemical

• , 480 mg weight) using water (3.6 μL, 0.5 equiv), 0.2 mL of 2-methyl-2-butanol (2M2B) as a LAG additive (η = 1.63) and 40 mg of CALB (Novozym 435, Novozymes, recombinant, expressed in Aspergillus niger, immobilized in acrylic resin, >10000 U/g) at 25 Hz during 30 min. Gratifyingly, 55% conversion to the

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

• underexplored [14], despite photocatalysis could clearly benefit from the excellent mixing under neat or liquid-assisted grinding (LAG) [15] conditions. Additionally, in contrast to solution-based methods, reactions by milling do not suffer from solubility restrictions due to the possibility to bring reactants

• mixture, however, the moderate yields for the products 3a–e, even in the presence of 1.5 equiv of 2, could have been the result of background reactions undergone by 1a–e under the reaction conditions, especially due to the rise in temperature observed upon light irradiation. As mentioned above, LAG, an

• alternative to the standard neat grinding, has become an useful parameter in mechanochemistry to control chemical selectivity and product composition by having catalytic volumes of organic solvent during the milling [24]. Here, a change in the milling approach from neat to LAG was anticipated to have the

NMR reaction monitoring in flow synthesis

• M. Victoria Gomez and
• Antonio de la Hoz

Beilstein J. Org. Chem. 2017, 13, 285–300, doi:10.3762/bjoc.13.31

• reaction mixture passes through the NMR instrument and is continuously analyzed. This method is called in-line analysis. This configuration minimises the time-lag between reaction and analysis. For on-line analysis the NMR system is not directly connected to the reaction system and the sample is

Nucleophilic displacement reactions of 5′-derivatised nucleosides in a vibration ball mill

• Olga Eguaogie,
• Patrick F. Conlon,
• Francesco Ravalico,
• Jamie S. T. Sweet,
• Thomas B. Elder,
• Louis P. Conway,
• Marc E. Lennon,
• David R. W. Hodgson and
• Joseph S. Vyle

Beilstein J. Org. Chem. 2017, 13, 87–92, doi:10.3762/bjoc.13.11

• ) remained untransformed during (dry) VBM or liquid-assisted grinding (LAG) in the presence of DMF with excess KSeCN (3 equiv). As found previously, the addition of catalytic TBAI (vide supra) did not alter this outcome nor did the use of a larger excess (5 equiv) of selenocyanate. The addition of DMF to the

• reaction of TsA (1b) with KSeCN suppressed the formation of a polar side-product (putative N3,5′-cyclonucleoside – also observed as the sole product using LAG in the absence of selenocyanate) sufficiently for the corresponding 5′-selenocyanate (3a) to be isolated in poor yield after LAG for 11 hours

• . Suspending the reaction mixture in methanol and quenching excess selenocyanate with benzyl bromide enabled pure 3a to be isolated following extensive purification. In contrast, LAG of TsT (1c) with DMF for 9 h achieved 90% conversion (by TLC) to a single product. Likewise, efficient (ca. 95%) conversions

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

• formation In 2009, Alvarez-Nunez et al. of Amgen used TSE to scale up the synthesis of a cocrystal which had already been reported to be synthesised successfully by ball milling (employing liquid-assisted grinding (LAG)). This was the first example demonstrating that mechanochemical synthesis could be

Poly(ethylene glycol)s as grinding additives in the mechanochemical preparation of highly functionalized 3,5-disubstituted hydantoins

• Andrea Mascitti,
• Massimiliano Lupacchini,
• Ruben Guerra,
• Ilya Taydakov,
• Lucia Tonucci,
• Nicola d’Alessandro,
• Frederic Lamaty,
• Jean Martinez and
• Evelina Colacino

Beilstein J. Org. Chem. 2017, 13, 19–25, doi:10.3762/bjoc.13.3

• investigated in the presence of various poly(ethylene) glycols (PEGs), as safe grinding assisting agents (liquid-assisted grinding, LAG). A comparative study under dry-grinding conditions was also performed. The results showed that the cyclization reaction was influenced by the amount of the PEG grinding

• agents. In general, cleaner reaction profiles were observed in the presence of PEGs, compared to dry-grinding procedures. Keywords: ball-milling; 1,1’-carbonyldiimidazole (CDI); hydantoins; mechanochemistry; liquid-assisted grinding (LAG); poly(ethylene) glycols (PEGs); Introduction Poly(ethylene

• physical aspects also connected to the intrinsic properties of the polymer. In addition, PEG polymers were demonstrated as a valid eco-friendly and safe alternative to classic solvents used in liquid-assisted-grinding procedures (LAG) [18][19][20][21][22] due to their low melting point (45–60 °C), enabling

Inhibition of peptide aggregation by means of enzymatic phosphorylation

• Kristin Folmert,
• Malgorzata Broncel,
• Hans v. Berlepsch,
• Christopher H. Ullrich,
• Mary-Ann Siegert and
• Beate Koksch

Beilstein J. Org. Chem. 2016, 12, 2462–2470, doi:10.3762/bjoc.12.240

• formation [49]. KFM6 shows a strongly increasing fluorescence signal without lag time, reaching a plateau after ten hours (Figure 2, circles). The displayed data indicate a fast amyloid growth process that appears to begin upon dissolution in buffer. This observation is in good agreement with the CD spectra

• , in which no lag time was observed. To discover the morphology of the amyloid fibrils, a TEM (transmission electron micrograph) was obtained at 24 hours of incubation (Figure 3a). The TEM shows typical amyloid morphologies such as extended tubular fibers, some of them ending in funnels. The

• order oligomers. Also no precipitation was observed. These results indicate high stability of the chemically phosphorylated peptide in comparison to the unphosphorylated analog. Discussion In the accepted model pathway of amyloid formation, a lag phase populated by functional soluble peptide structures

Antioxidant potential of curcumin-related compounds studied by chemiluminescence kinetics, chain-breaking efficiencies, scavenging activity (ORAC) and DFT calculations

• Adriana K. Slavova-Kazakova,
• Silvia E. Angelova,
• Timur L. Veprintsev,
• Petko Denev,
• Davide Fabbri,
• Maria Antonietta Dettori,
• Maria Kratchanova,
• Vladimir V. Naumov,
• Aleksei V. Trofimov,
• Rostislav F. Vasil’ev,
• Giovanna Delogu and
• Vessela D. Kancheva

Beilstein J. Org. Chem. 2015, 11, 1398–1411, doi:10.3762/bjoc.11.151

• of uninhibited oxidation one and a lag phase would be observed. We did not observe any lag phase in the presence of studied monomers and dimers at a 10-fold higher concentration in comparison to that of 13. This means that there should not be considerable differences between kFL, kAm, and kAd. The

The regulation and biosynthesis of antimycins

• Ryan F. Seipke and
• Matthew I. Hutchings

Beilstein J. Org. Chem. 2013, 9, 2556–2563, doi:10.3762/bjoc.9.290

• Hutchings, unpublished results). This lag between gene expression and antimycin production may be due to the complex biosynthetic machinery that needs to be assembled to first make the unusual starter unit 3-aminosalicylate and then finally assemble the antimycin scaffold. The down-regulation of all the ant

Temperature measurements with two different IR sensors in a continuous-flow microwave heated system

• Jonas Rydfjord,
• Fredrik Svensson,
• Magnus Fagrell,
• Jonas Sävmarker,
• Måns Thulin and
• Mats Larhed

Beilstein J. Org. Chem. 2013, 9, 2079–2087, doi:10.3762/bjoc.9.244

• adjusts power to reach set temperature it does not have to compensate for the lag that is created for IR sensor 1 when the reactor walls need to be heated. This characteristic might prove in handy for processes where a change in properties of the contents of the reactor happens suddenly as the control

Integrating reaction and analysis: investigation of higher-order reactions by cryogenic trapping

• Skrollan Stockinger and
• Oliver Trapp

Beilstein J. Org. Chem. 2013, 9, 1837–1842, doi:10.3762/bjoc.9.214

• significant increase in yield, which might be explained by a certain lag time in the formation of benzyne. Therefore, the benzenediazonium-2-carboxylate was injected first, followed by the anthracene derivative by using two syringes to avoid any product formation by contamination. It can be assumed that the

Mechanochemistry assisted asymmetric organocatalysis: A sustainable approach

• Pankaj Chauhan and
• Swapandeep Singh Chimni

Beilstein J. Org. Chem. 2012, 8, 2132–2141, doi:10.3762/bjoc.8.240

• grinding and liquid-assisted grinding (LAG) have been applied to the synthesis of mono- and bis(thiourea)s in quantitative yield by using the click coupling of aromatic or aliphatic diamines with aromatic isothiocyanates (Scheme 9) [54]. The mechanochemically prepared chiral molecules were applied as

• organocatalysts in an enantioselective MBH reaction and as cyanide ion sensors in organic solvents. Chiral bis-thiourea XI catalyses the MBH reaction of benzaldehyde (2b) and 2-cyclohexen-1-one (15) to provide MBH adduct 16 in 70% yield and 24% ee under neat grinding and LAG. Anhydride ring opening The

Self-assembled organic–inorganic magnetic hybrid adsorbent ferrite based on cyclodextrin nanoparticles

• Ângelo M. L. Denadai,
• Frederico B. De Sousa,
• Joel J. Passos,
• Fernando C. Guatimosim,
• Kirla D. Barbosa,
• Ana E. Burgos,
• Fernando Castro de Oliveira,
• Jeann C. da Silva,
• Bernardo R. A. Neves,
• Nelcy D. S. Mohallem and
• Rubén D. Sinisterra

Beilstein J. Org. Chem. 2012, 8, 1867–1876, doi:10.3762/bjoc.8.215

• with a Nanoscope IV MultiMode from Veeco Instruments operating in intermittent contact (tapping) mode, with standard Si probes. Phase-contrast images were acquired simultaneously with topographic images by monitoring, with a lock-in amplifier, the phase lag between the oscillation driver and the actual

Synthetic approaches to multifunctional indenes

• Neus Mesquida,
• Sara López-Pérez,
• Immaculada Dinarès and
• Ermitas Alcalde

Beilstein J. Org. Chem. 2011, 7, 1739–1744, doi:10.3762/bjoc.7.204

• approaches leading to these compounds lag behind those for heteroaromatic systems, e.g., indoles, being limited as it is by the scarce knowledge of indene chemistry in comparison with heterocyclic chemistry [3][17][18][19][20][21][22]. Moreover, chemical transformation by indenes, which could permit rapid

Insights into the mechanical properties of a silicone oil gel with a ‘latent’ gelator, 1-octadecylamine, and CO₂ as an ‘activator’

• Emiliano Carretti,
• Mathew George and
• Richard G. Weiss

Beilstein J. Org. Chem. 2010, 6, 984–991, doi:10.3762/bjoc.6.111

• lag between the applied shear stress and the related flow and from the ratio between the amplitudes of the imposed oscillation and the response of the gel. The complex viscosity was also calculated from Equation 1. G′ and G″ were measured over a 0.001–100 s−1 frequency range. The values of the stress