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

Electron-transfer-initiated benzoin- and Stetter-like reactions in packed-bed reactors for process intensification

• Anna Zaghi,
• Daniele Ragno,
• Graziano Di Carmine,
• Carmela De Risi,
• Olga Bortolini,
• Pier Paolo Giovannini,
• Giancarlo Fantin and
• Alessandro Massi

Beilstein J. Org. Chem. 2016, 12, 2719–2730, doi:10.3762/bjoc.12.268

• homogeneous NHCs [13][14]. On the other hand, heterogeneous catalysis in microstructured flow reactors represents a robust synthetic platform, with benefits over the corresponding batch processes such as catalyst stability, lower degradation of supports, and ease of scale-up with minimal changes to the

• -supported base. Together with the ease of product/promoter separation, an important benefit of the flow regime has been the significant long-term stability of the packing bed (ca. 5 five days on streams). Small-scale reactors have been described in this work; nevertheless, an easy scale-up of the disclosed

Continuous-flow synthesis of primary amines: Metal-free reduction of aliphatic and aromatic nitro derivatives with trichlorosilane

• Riccardo Porta,
• Alessandra Puglisi,
• Giacomo Colombo,
• Sergio Rossi and
• Maurizio Benaglia

Beilstein J. Org. Chem. 2016, 12, 2614–2619, doi:10.3762/bjoc.12.257

• . Flow chemistry has recently emerged as a powerful technology in synthetic chemistry [12] as it can reduce risks associated to the use of hazardous chemicals and favors reaction scale-up [13][14][15][16][17]. The possibility to efficiently perform nitro reduction in continuo would make the

• transformation safer and more appealing in view of an industrial application and a possible scale-up of the process [18][19][20]. Herein we report a very convenient, metal-free reduction of both aromatic and aliphatic nitro derivatives, including chiral compounds, to amines with HSiCl3 under continuous-flow

• the reaction (the first few hours). Having demonstrated that the flow transformation is very fast we next explored reaction scale-up employing a bigger flow reactor (5 mL PTFE reactor, i.d. = 2.54 mm, l = 100 cm), in order to increase the productivity of the process. Using the same reaction set-up

Development of a continuous process for α-thio-β-chloroacrylamide synthesis with enhanced control of a cascade transformation

• Olga C. Dennehy,
• Valérie M. Y. Cacheux,
• Benjamin J. Deadman,
• Denis Lynch,
• Stuart G. Collins,
• Humphrey A. Moynihan and
• Anita R. Maguire

Beilstein J. Org. Chem. 2016, 12, 2511–2522, doi:10.3762/bjoc.12.246

• into an oil bath at 90 °C (Scheme 2). While this route has consistently provided a robust means of generating the desired β-chloroacrylamides at scales of 1–10 g, it suffers from several disadvantages which impact on the ease of scale-up. The preparation of the α-chloroamide 1 is exothermic and

• requires significant external cooling, an undesirable feature for scale-up. The synthesis of the α-thioamide 2 involves prior generation of fresh sodium ethoxide from sodium metal. Furthermore, this α-thioamide protocol, at high pH, ordinarily does not go to completion, leaving unreacted starting material

• efficient rapid heating poses practical difficulties for scale-up and, furthermore, chromatographic separation is required to remove product impurities. The nature of the aforementioned difficulties outlined are, however, largely specific to the scale-up of batch chemistry. A continuous processing approach

Facile synthesis of indolo[3,2-a]carbazoles via Pd-catalyzed twofold oxidative cyclization

• Chao Yang,
• Kai Lin,
• Lan Huang,
• Wei-dong Pan and
• Sheng Liu

Beilstein J. Org. Chem. 2016, 12, 2490–2494, doi:10.3762/bjoc.12.243

• sequence to deliver 9-methoxycarbonyl indolo[3,2-a]carbazole derivatives. Previous literature aimed at providing rapid and efficient access to indolo[3,2-a]carbazoles, however, most of them have some disadvantages. Few methods were reported to be suitable for scale-up preparation and the introduction of

• material and the product may occur. To examine whether the desired transformation was suitable for scale-up, a gram-scale synthesis of 2a was also achieved (Table 1, entry 9). With the optimized conditions in hand, the generality and scope of the reaction were also examined (Scheme 3). A range of

Efficient mechanochemical synthesis of regioselective persubstituted cyclodextrins

• Laszlo Jicsinszky,
• Marina Caporaso,
• Katia Martina,
• Emanuela Calcio Gaudino and
• Giancarlo Cravotto

Beilstein J. Org. Chem. 2016, 12, 2364–2371, doi:10.3762/bjoc.12.230

• conditions nor the purifications were optimized in any terms the presented results can serve as starting point to develop more environmentally benign synthetic methods of important CD derivatives. The well-established engineering of HEBM reactions makes them easy to scale-up, while simplified work-up

• removal found in the small scale, as it becomes clear in the scale-up experiments (entries 4 and 11 in Table 1). Although the preparation of 6I-monoazido-6I-monodeoxy-β-CD [22] was very effective, the analogue reactions with per-6-substituted CDs (4a and 4b) were less efficient. Either the reaction did

• needed to get less deficit in the precipitates. Considerable losses during filtrations were found in the small-scale cases, which significantly reduced the yields because of the inevitably used diluted solutions. The ten-fold scale up (entry 28 in Table 1) further simplified the product isolation because

High performance p-type molecular electron donors for OPV applications via alkylthiophene catenation chromophore extension

• Paul B. Geraghty,
• Calvin Lee,
• Jegadesan Subbiah,
• Wallace W. H. Wong,
• James L. Banal,
• Mohammed A. Jameel,
• Trevor A. Smith and
• David J. Jones

Beilstein J. Org. Chem. 2016, 12, 2298–2314, doi:10.3762/bjoc.12.223

• active layer up to 310 nm thick. In this case fill-factors (FF) remain above 70%. However, OSC devices containing BTR are not stable to thermal annealing, a requirement for scale up using common printing processes, where temperatures >80 °C are required for drying or annealing of printed layers [15]. BTR

• has extremely interesting properties worth further study and leads to three key questions; Synthesis: Can we simplify the synthesis of BTR removing some chromatographic purification steps and use of toxic tin containing Stille condensation reactions? Scale-up: Can we develop a multi-gram synthesis

Economical and scalable synthesis of 6-amino-2-cyanobenzothiazole

• Jacob R. Hauser,
• Hester A. Beard,
• Mary E. Bayana,
• Katherine E. Jolley,
• Stuart L. Warriner and
• Robin S. Bon

Beilstein J. Org. Chem. 2016, 12, 2019–2025, doi:10.3762/bjoc.12.189

• ), which has an amine handle for straight-forward derivatisation. Here we present an economical and scalable synthesis of ACBT based on a cyanation catalysed by 1,4-diazabicyclo[2.2.2]octane (DABCO), and discuss its advantages for scale-up over previously reported routes. Keywords: ACBT; cyanation; 2

• variable yields (typically 30–50% in our hands). In addition, because DMSO can quickly penetrate the skin, working with KCN in DMSO requires substantial safety measures. Therefore, this route does not allow straightforward scale-up under laboratory conditions. Prescher and co-workers reported an

• . In view of scale-up of the DABCO-catalysed cyanation of 6, an alternative solvent (mixture) was sought in order to eliminate safety issues and work-up problems resulting from the use of DMSO. An initial attempt to run the reaction in water failed because of the low aqueous solubility of 6 – resulting

The in situ generation and reactive quench of diazonium compounds in the synthesis of azo compounds in microreactors

• Faith M. Akwi and
• Paul Watts

Beilstein J. Org. Chem. 2016, 12, 1987–2004, doi:10.3762/bjoc.12.186

• reaction conversions ranging between 66–91% were attained. Keywords: azo coupling; diazotization; microreactor; scale up; Introduction Going green, a familiar catch phrase in the chemical industry, in addition to environment protection laws have influenced and also triggered the development of cleaner

• investigative research involving the synthesis of two azo pigments (yellow and red pigments) in microreactors [24], demonstrated that scaling out in the microreactors provided better and more consistent quality of the pigments as compared to scale up in the batch vessels. Similarly, yellow pigment 12 (15) was

• reaction. In addition, industry always questions why reactions are done in micro structured reactors rather than simple tubular reactors. As such, we extended this investigation to study the optimized conditions obtained within the LTF microreactors within PTFE tubing (i.d. 1.5 mm) in order to scale up the

Catalytic Chan–Lam coupling using a ‘tube-in-tube’ reactor to deliver molecular oxygen as an oxidant

• Carl J. Mallia,
• Paul M. Burton,
• Alexander M. R. Smith,
• Gary C. Walter and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2016, 12, 1598–1607, doi:10.3762/bjoc.12.156

• characteristic NOESY signal encircled. Substrates that gave no products in flow. Comparison of early C–N and C–O coupling reactions. Scope of the catalytic Chan–Lam reaction in continuous flow. Syntheses of substrate 39. Scale-up procedure for 19. Optimisation of the Chan–Lam reaction in continuous flow

Flow carbonylation of sterically hindered ortho-substituted iodoarenes

• Carl J. Mallia,
• Gary C. Walter and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2016, 12, 1503–1511, doi:10.3762/bjoc.12.147

• smaller when larger volume flasks are used as in scale up procedures making the mass transfer even less efficient. In contrast, high interfacial areas can be achieved in flow reactors especially microchannel reactors (a = 3400–18000 m2 m−3) [30], which increases the mass transfer and thus helps solubilise

• turnaround time is much longer. This makes the flow reactor more efficient in terms of processing time. Additionally, the added safety and potential benefits regarding scale up associated with the flow reactor makes this even more favourable. Having identified a set of reaction conditions for successful

• of ortho-substituted substrates giving moderate to good yields. Comparison of 22 with 32 also showed that the steric encumbrance on the ortho position has an effect on the yield even when other electronic effects are in place such as those coming from the additional aromatic ring attached. A scale-up