β-Hydroxy sulfides and their syntheses

• Mokgethwa B. Marakalala,
• Edwin M. Mmutlane and
• Henok H. Kinfe

Beilstein J. Org. Chem. 2018, 14, 1668–1692, doi:10.3762/bjoc.14.143

• . The arylthiols bearing chloro and fluoro substituents gave the expected β-hydroxy sulfides in moderate yields while the much deactivated nitro-thiophenol did not lead to any product formation. The protocol allowed easy scale-up to gram quantities. The results strongly supported a free radical

Anomeric modification of carbohydrates using the Mitsunobu reaction

• Julia Hain,
• Patrick Rollin,
• Werner Klaffke and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1619–1636, doi:10.3762/bjoc.14.138

• text books claim. Unfortunately, the Mitsunobu reaction is uneasy to scale up and this is probably one of the biggest obstacles for a broad and also technical use of this reaction. Nevertheless, this review proves that in the glycosciences, the Mitsunobu reaction must not be overlooked as it is an

Direct electrochemical generation of organic carbonates by dehydrogenative coupling

• Tile Gieshoff,
• Vinh Trieu,
• Jan Heijl and
• Siegfried R. Waldvogel

Beilstein J. Org. Chem. 2018, 14, 1578–1582, doi:10.3762/bjoc.14.135

• within scale-up, when a significant effect of the electrode distance occurred (Figure 2). To generate a sufficient amount of material for work-up studies, we conducted conversions in 25 mL beaker-type cells. However, neither product formation nor conversion were observed. Since all parameters were

An efficient and facile access to highly functionalized pyrrole derivatives

• Meng Gao,
• Wenting Zhao,
• Hongyi Zhao,
• Ziyun Lin,
• Dongfeng Zhang and
• Haihong Huang

Beilstein J. Org. Chem. 2018, 14, 884–890, doi:10.3762/bjoc.14.75

• another simple dipolarophile was also examined; the target product 12k was prepared smoothly in high yield (74%). This concise and efficient protocol displays the potentiality for scale-up synthesis of pyrrolo[3,4-c]pyrrole-1,3-diones. Having the pyrrolo[3,4-c]pyrrole-1,3-diones with diversified

Continuous-flow retro-Diels–Alder reaction: an efficient method for the preparation of pyrimidinone derivatives

• Imane Nekkaa,
• Márta Palkó,
• István M. Mándity and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2018, 14, 318–324, doi:10.3762/bjoc.14.20

• optimization, acceleration [6], and easy scale-up with a wide and growing range of chemical transformations in combination with an inherently safe and green nature [7][8][9][10][11][12]. Advantageously, safety issues are complied with excellent mixing and heat transfer [7][8][9][10][11][12][13][14]. These

Halogen-containing thiazole orange analogues – new fluorogenic DNA stains

• Aleksey A. Vasilev,
• Meglena I. Kandinska,
• Stanimir S. Stoyanov,
• Stanislava B. Yordanova,
• David Sucunza,
• Juan J. Vaquero,
• Obis D. Castaño,
• Stanislav Baluschev and
• Silvia E. Angelova

Beilstein J. Org. Chem. 2017, 13, 2902–2914, doi:10.3762/bjoc.13.283

• -condensation of the resulting quaternary products. Carrying out the reaction in bulk without solvents allows scale-up of the quaternary salt synthesis and prevents possible environmental pollution. The known synthetic procedure [50][51] for the target dyes (Scheme 3) was modified to obtain the model compound

• solvents in organic synthesis. The reaction in water as a solvent provided moderate yields (procedures B1 and B2), but the subsequent scale-up of these reactions could be favorable on using intermediates with better water solubility. The best reaction yields for TO-7Cl were obtained on using procedure C1

The synthesis of the 2,3-difluorobutan-1,4-diol diastereomers

• Robert Szpera,
• Nadia Kovalenko,
• Kalaiselvi Natarajan,
• Nina Paillard and
• Bruno Linclau

Beilstein J. Org. Chem. 2017, 13, 2883–2887, doi:10.3762/bjoc.13.280

• protecting group resulted in a significant increase in mass, and therefore, chromatographic purification of the protected intermediates upon scale-up was inconvenient. As previously reported [17], epoxide opening of cis-2 with Olah’s reagent (HF·py) led to an 80% yield of the fluorohydrin after just three

• , on scale-up this proved inconvenient due to the large volumes of solvent required, and so these impurities were precipitated out the reaction mixture by cooling to 0 °C and collected by filtration through Celite. After work-up, the obtained epoxide was of high purity and no additional chromatographic

• ppm) [17]. Upon scale-up of the reaction to 10 g of (±)-trans-2, a similarly high yield of 90% (crude) was obtained, which again could be used directly in the next step without purification. Conversion of fluorohydrin (±)-anti-3 to difluoride (±)-syn-4 under the same conditions as shown in Scheme 2

A concise flow synthesis of indole-3-carboxylic ester and its derivatisation to an auxin mimic

• Marcus Baumann,
• Ian R. Baxendale and
• Fabien Deplante

Beilstein J. Org. Chem. 2017, 13, 2549–2560, doi:10.3762/bjoc.13.251

• Marcus Baumann Ian R. Baxendale Fabien Deplante Department of Chemistry, University of Durham, South Road, Durham, Durham, DH1 3LE, UK 10.3762/bjoc.13.251 Abstract An assembled suite of flow-based transformations have been used to rapidly scale-up the production of a novel auxin mimic-based

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

• both oxidation and acid catalyzed processes. Among all the known oxidative transformations, the oxidation of alcohols to ketones and aldehydes have gained a lot of attention for the research community due to its broad range of industrial applications [38][39]. Nonetheless, the scale up of the oxidation

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

• Aleksanyan and co-workers reported the first gram-scale synthesis of a PdII organometallic pincer complex under mechanomilling via C–H bond activation. After successful isolation of the PdII pincer complex by grinding of bis(thiocarbamate) and PdCl2(NCPh)2 they could scale up the reaction up to 1.76 mmol

Influence of the milling parameters on the nucleophilic substitution reaction of activated β-cyclodextrins

• László Jicsinszky,
• Kata Tuza,
• Giancarlo Cravotto,
• Andrea Porcheddu,
• Francesco Delogu and
• Evelina Colacino

Beilstein J. Org. Chem. 2017, 13, 1893–1899, doi:10.3762/bjoc.13.184

• materials, ball number and size, ball-to-powder mass ratio, the fraction of reactor volume occupied by balls and the reactor volume itself. Results and Discussion We previously reported [13] a successful scale-up monoazidation reaction of Ts-β-CD (the reaction scale was 6.5 g, 5 mmol) in a ball-mill

Accessing simply-substituted 4-hydroxytetrahydroisoquinolines via Pomeranz–Fritsch–Bobbitt reaction with non-activated and moderately-activated systems

• Marco Mottinelli,
• Mathew P. Leese and
• Barry V. L. Potter

Beilstein J. Org. Chem. 2017, 13, 1871–1878, doi:10.3762/bjoc.13.182

• catalyze the cyclization of 2-MeO compound 9n, rendering the target THIQ 10n inaccessible by this approach. In certain cases, during scale-up of the reaction to a gram scale, a minor product became clearly identifiable and could sometimes be isolated. Whenever the cyclization was possible in both the para

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

• ’) in the vial was required to accommodate this increase in pressure. A larger vial (25 mL) was then employed, which was able to sustain the pressure of the water vapour produced in the system, and with that there was a 5-fold scale-up of the reaction mixture from ca. 0.2 g to ca. 1.0 g. After 60

• carried out (where grinding results in degradation of the material). Finally, as with ball milling, there is potential for the scale-up of sonochemical reactions, therefore aiding in the drive towards sustainable chemistry. Typical laboratory employed planetary ball mill and ultrasonic bath. o-Vanillin in

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

• benzoxazinoindolines 85 to benzoxazinoindoles 86 (found in elbasvir (87), a component of zepatier®, a combination therapeutic drug approved by FDA for curing Hepatitis C, Scheme 30). The robustness of the strategy is exemplified by demonstrating a successful scale-up reaction of 86 in 0.5 kg scale. The putative

• other chronic and acute neurogenerative diseases [99]. This molecule reached the clinical development phase, consequently a safe, robust and economic scale-up process was investigated by the researcher as the original process was incompatible towards scale-up. The investigation indeed provided a better

• scale-up process, where the key reaction, a Zeigler coupling, of an early trifluoromethylimidazole intermediate 100 with commercially available 2-chloro-5-fluoropyrimidine afforded 101 (a compound with partially saturated pyrimidine framework). An aerobic oxidative dehydrogenation of 101 in the presence

Synthesis of oligonucleotides on a soluble support

• Harri Lönnberg

Beilstein J. Org. Chem. 2017, 13, 1368–1387, doi:10.3762/bjoc.13.134

• blocks, (ii) the scale up procedure would be more straightforward and (iii) expensive solid support material is not needed. In addition, the possibility to characterize the growing chain by mass or NMR spectroscopy after each coupling is an attractive feature, although not possible with all soluble

G-Protein coupled receptors: answers from simulations

• Timothy Clark

Beilstein J. Org. Chem. 2017, 13, 1071–1078, doi:10.3762/bjoc.13.106

• specialized hardware such as Anton [25] but are less effective on more conventional massively parallel supercomputers because the simulations only scale up to a relatively limited number of CPUs or GPUs [35]. Luckily, of the many enhanced-sampling techniques [35], modern variations of metadynamics [27] can

A concise and practical stereoselective synthesis of ipragliflozin L-proline

• Shuai Ma,
• Zhenren Liu,
• Jing Pan,
• Shunli Zhang and
• Weicheng Zhou

Beilstein J. Org. Chem. 2017, 13, 1064–1070, doi:10.3762/bjoc.13.105

• prepare dapagliflozin and canagliflozin. However, these approaches might be difficult to scale up because of the involvements of complex synthetic procedures, chromatographic purification or expensive catalysts and ligands. Gong et al. [15] reported an approach to synthesise C-aryl glycosides based on a

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97

• provide solutions for scale-up of lab processes [61][62][63][64][65][66][67] usually their hands-on experience to decide the control strategy while automating a flow chemistry always offers better solutions than what one expects theoretically. Before analysing these complex syntheses, it is worth

• controlling and maintaining the process at a steady state. Here we have suggested some simple control strategies which can be adapted even for scale-up. With each process having different chemistries, unit operations and operating conditions, the operating protocol and control strategy may change every time

• fluid flow rate. This will help to measure the heat duty for the specific reaction, which can be used for estimating the enthalpy change in the specific reaction. This data is immensely useful for scale-up of this approach. A back pressure regulator (BPR) can be used to maintain the desired set pressure

Solid-phase enrichment and analysis of electrophilic natural products

• Frank Wesche,
• Yue He and
• Helge B. Bode

Beilstein J. Org. Chem. 2017, 13, 405–409, doi:10.3762/bjoc.13.43

• combination with labeling experiments even the nature of the parent natural product could be revealed. Moreover, a possible scale-up of this procedure should enable the preparative purification of yet unidentified compounds as well as the structural confirmation of the identified structures. This approach can

A chemoselective and continuous synthesis of m-sulfamoylbenzamide analogues

• Arno Verlee,
• Thomas Heugebaert,
• Tom van der Meer,
• Pavel I. Kerchev,
• Frank Van Breusegem and
• Christian V. Stevens

Beilstein J. Org. Chem. 2017, 13, 303–312, doi:10.3762/bjoc.13.33

• suitable for automation, thus allowing the fast synthesis of compound libraries, but as opposed to, e.g., combinatorial chemistry, the developed protocols are directly useful for scale-up. A class of small molecules where these principles can apply for are m-sulfamoylbenzamides. These compounds proved to

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

• , analysis and work-up can be performed in an automatic and continuous manner, but optimization and scale-up represent a new step forward towards the full automation of the chemical process [3]. The final objective is to save time for chemists to focus on the more technical work and to spend their time

Continuous-flow synthesis of highly functionalized imidazo-oxadiazoles facilitated by microfluidic extraction

• Ananda Herath and
• Nicholas D. P. Cosford

Beilstein J. Org. Chem. 2017, 13, 239–246, doi:10.3762/bjoc.13.26

• less attractive during scale-up due to the difficulty of removal of these solvents during purification. Consequently the current method is limited to small scale library synthesis. Therefore, our next goal was to convert this microfluidic procedure to a sequence that would deliver compounds on a larger

• reaction steps requiring work-up and purification of several intermediates. Furthermore, liquid–liquid microextraction removes high boiling point solvent and impurities from the product. Finally, this new process with liquid–liquid extraction allows easy scale-up and eliminates the tedious high boiling

Diels–Alder reactions of myrcene using intensified continuous-flow reactors

• Christian H. Hornung,
• Miguel Á. Álvarez-Diéguez,
• Thomas M. Kohl and
• John Tsanaktsidis

Beilstein J. Org. Chem. 2017, 13, 120–126, doi:10.3762/bjoc.13.15

• continuous-flow approach provides a facile alternative scale-up route to conventional batch processing, and it helps to intensify the synthesis protocol by applying higher reaction temperatures and shorter reaction times. Keywords: continuous processing; flow chemistry; renewable feedstock; surfactant

• R2/R4 tubular flow reactor to a reaction volume of typically 20 mL and then on a Chemtrix Plantrix® MR260 plate flow reactor to a reaction volume of typically 200 mL (see also experimental section). The results from these continuous-flow experiments are shown in Table 3. The 10-times scale-up in the

• tubular flow reactor and the 100 times scale-up in the plate flow reactor resulted in similar, if not slightly higher conversions than the batch experiments (see Figure 2). The two continuous reactors produced high-quality material at steady state conditions. The reaction profile in the plate flow reactor

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

• avoided. In summary, extrusion is a technique that has great potential for use in organic synthesis. It has already been demonstrated as a method to scale up synthesis carried out by ball milling, therefore there is very little preventing its use for the organic reactions that have been reported to be

The digital code driven autonomous synthesis of ibuprofen automated in a 3D-printer-based robot

• Philip J. Kitson,
• Stefan Glatzel and
• Leroy Cronin

Beilstein J. Org. Chem. 2016, 12, 2776–2783, doi:10.3762/bjoc.12.276

• reaction solutions deposited. These could be easily tuned in the control software and the volumes required for each of these scales are summarised in Table 2. The yields from each of the scales of reaction described were similar (see Supporting Information File 1), however, it was found that further scale

• -up by increasing the reaction vessel volume (a fourth reaction vessel, R4, was also produced with an internal volume of 28.12 mL, see Supporting Information File 2 for dimensions) lead to reduced yields and longer reaction times. The maximum yield obtained using larger volume reactor vessels was