Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivatives

• Alexander Leslie,
• Thomas S. Moody,
• Megan Smyth,
• Scott Wharry and
• Marcus Baumann

Beilstein J. Org. Chem. 2021, 17, 379–384, doi:10.3762/bjoc.17.33

• purification of a small library of valuable Cbz-carbamates (see Figure 1). Furthermore, the CALB column was effectively used over several days after purging with toluene to prevent cross contamination. The scale-up of this flow process was demonstrated on a 100 mmol scale showcasing the robust nature of this

Dawn of a new era in industrial photochemistry: the scale-up of micro- and mesostructured photoreactors

• Emine Kayahan,
• Mathias Jacobs,
• Leen Braeken,
• Leen C.J. Thomassen,
• Simon Kuhn,
• Tom van Gerven and
• M. Enis Leblebici

Beilstein J. Org. Chem. 2020, 16, 2484–2504, doi:10.3762/bjoc.16.202

• flow photoreactors. In this work, we are reviewing structured photoreactors by elaborating on the bottleneck of this field: the development of an efficient scale-up strategy. In line with this, micro- and mesostructured bench-scale photoreactors were evaluated based on a new benchmark called

• concentration of the photoactive molecule is also crucial for an efficient photoreactor operation. In this paper, we are aiming to give a comprehensive understanding for scale-up strategies by benchmarking selected photoreactors and by discussing transport phenomena in several other photoreactors. Keywords

• : microreactor; microreactor scale-up; monolith reactors; packed bed reactor; photoreactor scale-up; Review Introduction In the traditional chemical industry, thermochemical activation routes are mostly preferred. Light can also activate some molecules, which leads to fast and selective reaction pathways

A proposed sustainability index for synthesis plans based on input provenance and output fate: application to academic and industrial synthesis plans for vanillin as a case study

• John Andraos

Beilstein J. Org. Chem. 2020, 16, 2346–2362, doi:10.3762/bjoc.16.196

• any chemist or chemical engineer, in this work we introduce a quantitative description of sustainability that is directly applicable to assess synthesis plans. Synthesis plans represent the heart and soul of what chemists create in the laboratory and chemical engineers scale up and optimize in the

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

• Shahboz Yakubov and
• Joshua P. Barham

Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

• photochemistry with near-UV behaves similar to UV photochemistry. On the other hand, photocatalysts typically used in PRC possess very high extinction coefficients, leading to a strong visible light absorption and reactions that suffer more on a scale-up due to the exponential relationship between the

When metal-catalyzed C–H functionalization meets visible-light photocatalysis

• Lucas Guillemard and
• Joanna Wencel-Delord

Beilstein J. Org. Chem. 2020, 16, 1754–1804, doi:10.3762/bjoc.16.147

• , isolated in moderate to good yields. A possible gram scale-up synthesis was also accomplished. Within the mechanistic cycle, after initial vinylic C–H bond activation and insertion of CO into the C–Pd bond, the acylpalladium intermediate is converted into its conjugated analog under DABCO assistance

Mechanochemical green synthesis of hyper-crosslinked cyclodextrin polymers

• Alberto Rubin Pedrazzo,
• Fabrizio Caldera,
• Marco Zanetti,
• Silvia Lucia Appleton,
• Nilesh Kumar Dhakar and
• Francesco Trotta

Beilstein J. Org. Chem. 2020, 16, 1554–1563, doi:10.3762/bjoc.16.127

• essential for the use of nanosponges in the biomedical field. In addition, these synthetic procedures may also not be convenient for a possible future scale up of the reaction, as huge amounts of solvent have to be disposed of. Moreover, organic solvents are expensive and DMSO and DMF are difficult to

Photocatalytic trifluoromethoxylation of arenes and heteroarenes in continuous-flow

• Alexander V. Nyuchev,
• Ting Wan,
• Borja Cendón,
• Carlo Sambiagio,
• Job J. C. Struijs,
• Michelle Ho,
• Moisés Gulías,
• Ying Wang and
• Timothy Noël

Beilstein J. Org. Chem. 2020, 16, 1305–1312, doi:10.3762/bjoc.16.111

• and heteroarenes. The use of flow photochemistry allows the reaction to occur 16 times faster than in batch, while at the same time achieving similar yields. Thanks to the intrinsic properties of microflow systems, especially for the scale-up of photochemical processes, we anticipate this procedure

Synthesis of esters of diaminotruxillic bis-amino acids by Pd-mediated photocycloaddition of analogs of the Kaede protein chromophore

• Esteban P. Urriolabeitia,
• Pablo Sánchez,
• Alexandra Pop,
• Cristian Silvestru,
• Eduardo Laga,
• Ana I. Jiménez and
• Carlos Cativiela

Beilstein J. Org. Chem. 2020, 16, 1111–1123, doi:10.3762/bjoc.16.98

• is remarkable that the C–H activation allows in this case scale-up of the reaction without a loss of yield. For oxazolone 2h the reaction was carried out using 4.3 mmol of starting material and the final yield of analytically pure 3h was 94% (see Experimental). The characterization of complexes 3

• approach allows the scale-up of the reaction without loss of yield of the final products. Experimental General methods Solvents were obtained from commercial sources and used without further purification. All reactions were performed without special precautions against water and moisture. Thin-layer

A method to determine the correct photocatalyst concentration for photooxidation reactions conducted in continuous flow reactors

• Clemens R. Horn and
• Sylvain Gremetz

Beilstein J. Org. Chem. 2020, 16, 871–879, doi:10.3762/bjoc.16.78

• overcome the difficulties that occur upon scale-up. The most desirable approach for industrial-scale reactions is described by the quote “the best approach to the scale-up of a photoreaction seems to be the enlarging of a laboratory-type prototype reactor, with the important parameters being changed as

• little as possible” [8]. This phrase describes the approach used to scale up flow reactors to an industrial scale [9][10]. This is particularly true when it comes to biphasic reactions, like a gas/liquid reaction as is the case for photooxidations [11]. An interesting aspect of photooxidations is that

• complicate the scale-up of the light source and design of the reactor. LED sources have continuously been evolving and will continue to do so because when being employed, the light source is no longer a limiting factor in the design of a larger-scale photoreactor setup [18]. Since an LED provides a narrower

Asymmetric synthesis of CF₂-functionalized aziridines by combined strong Brønsted acid catalysis

• Xing-Fa Tan,
• Fa-Guang Zhang and
• Jun-An Ma

Beilstein J. Org. Chem. 2020, 16, 638–644, doi:10.3762/bjoc.16.60

• . Scale-up experiment to 4a and further synthetic transformations. Representative screening results of the asymmetric aziridination reaction of PhSO2CF2CHN2.a Supporting Information Supporting Information File 244: Experimental procedures, compound characterization, NMR spectra of all new compounds, and

Recent advances in photocatalyzed reactions using well-defined copper(I) complexes

• Mingbing Zhong,
• Xavier Pannecoucke,
• Philippe Jubault and
• Thomas Poisson

Beilstein J. Org. Chem. 2020, 16, 451–481, doi:10.3762/bjoc.16.42

• straightforward scale-up of the method (up to 5 g). Mechanistic studies were carried out, suggesting a possible [Cu(I)]/[Cu(I)]*/[Cu(0)] reaction manifold. The copper photocatalyst in the excited state is reduced to the [Cu(0)] complex by the sacrificial organic reductant DIPEA. The in situ-formed [Cu(0)] species

Photophysics and photochemistry of NIR absorbers derived from cyanines: key to new technologies based on chemistry 4.0

• Bernd Strehmel,
• Christian Schmitz,
• Ceren Kütahya,
• Yulian Pang,
• Anke Drewitz and
• Heinz Mustroph

Beilstein J. Org. Chem. 2020, 16, 415–444, doi:10.3762/bjoc.16.40

Safe and highly efficient adaptation of potentially explosive azide chemistry involved in the synthesis of Tamiflu using continuous-flow technology

• Cloudius R. Sagandira and
• Paul Watts

Beilstein J. Org. Chem. 2019, 15, 2577–2589, doi:10.3762/bjoc.15.251

• , more than 60 synthetic routes have been developed to date, however, most of the synthetic routes utilise the potentially hazardous azide chemistry making them not green, thus not amenable to easy scale up. Consequently, this study exclusively demonstrated safe and efficient handling of potentially

• firm that specialises in azide chemistry to develop its industrial process [1][2][6][9]. Numerous reported routes demonstrate amazing potential and ingenuity in the Tamiflu molecule assembly. However, most of them are not amenable to easy scale-up due to the safety concerns associated with azide

• large scale synthesis in batch systems on the basis of safety concerns poised by the use of the potentially explosive azide chemistry and other hazardous chemistry. Therefore, problems inherent in scale-up are effectively eliminated or reduced, making microreactor technology a viable tool in the

Isolation of fungi using the diffusion chamber device FIND technology

• Benjamin Libor,
• Henrik Harms,
• Stefan Kehraus,
• Ekaterina Egereva,
• Max Crüsemann and
• Gabriele M. König

Beilstein J. Org. Chem. 2019, 15, 2191–2203, doi:10.3762/bjoc.15.216

• prevent bacterial growth. For scale-up fermentation, H. cf. alpina was cultivated in 42 Fernbach flasks containing 150 mL of BMS agar medium (20 g biomalt in 1 L artificial seawater) each at 25 °C for 28 days. The fermented material of every two Fernbach flasks was extracted three times with 300 mL ethyl

Metal-free mechanochemical oxidations in Ertalyte^® jars

• Andrea Porcheddu,
• Francesco Delogu,
• Lidia De Luca,
• Claudia Fattuoni and
• Evelina Colacino

Beilstein J. Org. Chem. 2019, 15, 1786–1794, doi:10.3762/bjoc.15.172

• . Finally, we investigated if this protocol could be potentially implemented on a larger scale. Pleasingly, we were able to scale-up the oxidation of 1a and 11a from a 1 mmol up to a 10 mmol scale without any significant drop in terms of purity and yield, thus confirming the method’s potential adaptability

A novel three-component reaction between isocyanides, alcohols or thiols and elemental sulfur: a mild, catalyst-free approach towards O-thiocarbamates and dithiocarbamates

• András György Németh,
• György Miklós Keserű and
• Péter Ábrányi-Balogh

Beilstein J. Org. Chem. 2019, 15, 1523–1533, doi:10.3762/bjoc.15.155

• characterized by 1H NMR, 13C NMR, HRMS and melting point. After the successful application of various nucleophiles, it was our intention to investigate the scalability of the procedure. Thus, a twenty-fold scale-up of the reaction between the isocyanide 1a, sulfur and methanol (2a) was performed (Scheme 5). In

Reaction of oxiranes with cyclodextrins under high-energy ball-milling conditions

• László Jicsinszky,
• Federica Calsolaro,
• Katia Martina,
• Fabio Bucciol,
• Maela Manzoli and
• Giancarlo Cravotto

Beilstein J. Org. Chem. 2019, 15, 1448–1459, doi:10.3762/bjoc.15.145

• challenging. Achieving a uniform insoluble CDP particle size is difficult and usually requires special, poorly transferable techniques [13][14][16][20]. The drawbacks of classical derivatisation methods include their problematic scale-up, which explains the limited number of sources of insoluble CDPs and also

• considered negligible. Salt formation in the 10-fold scaled-up synthesis of the β-CD polymer resulted in some materials that became stuck on the jar wall. However, these were considerably easier to remove than the salts of hydrated CDs. The scale-up experiment (20 mmol scale) did not give a significantly

• stainless-steel balls (m = 44.1 g, in which ø = 5 mm, m = 28.1 g and 550 ø = 1–1.2 mm, m = 16.0 g) at 650 rpm for various time periods. The rotation direction was changed every 15 min (3 min during CD-Na salt preparation) with 3 seconds of silent periods between the alternating rotations. The scale-up of

Mechanochemical synthesis of hyper-crosslinked polymers: influences on their pore structure and adsorption behaviour for organic vapors

• Sven Grätz,
• Sebastian Zink,
• Hanna Kraffczyk,
• Marcus Rose and
• Lars Borchardt

Beilstein J. Org. Chem. 2019, 15, 1154–1161, doi:10.3762/bjoc.15.112

• that even small amounts of the monomer (3.2 mmol) lead to a swift and rise in vessel pressure exceeding 12 bar (Figure 3A) caused by the released HCl in the course of the reaction. This behaviour can be handled under laboratory conditions but is hampering the potential scale up of the process. In the

An improved synthesis of adefovir and related analogues

• David J. Jones,
• Eileen M. O’Leary and
• Timothy P. O’Sullivan

Beilstein J. Org. Chem. 2019, 15, 801–810, doi:10.3762/bjoc.15.77

• a sticky resin on exposure to atmospheric moisture. This resin hinders the isolation of phosphonate 6 and stymies scale-up. Finally, several byproducts, including the ethyl ether of 4 and the hemi-dealkylated ester of 6, are produced during this reaction, further reducing the atom economy of this

An efficient and concise access to 2-amino-4H-benzothiopyran-4-one derivatives

• Peng Li,
• Yongqi Wu,
• Tingting Zhang,
• Chen Ma,
• Ziyun Lin,
• Gang Li and
• Haihong Huang

Beilstein J. Org. Chem. 2019, 15, 703–709, doi:10.3762/bjoc.15.65

• and the substrate scope in terms of electronic properties of the substituents of the benzothiopyranone is broad. The ten grams scale-up synthesis of the representative compounds 4a and 4d was implemented to show the practical application of this reaction, which afforded the corresponding compounds in

• good yields and excellent chemical purity without requiring column chromatographical purification. Keywords: 2-amino-4H-benzothiopyran-4-ones; addition–elimination; scale-up synthesis; sulfinyl group; Introduction Benzothiopyranones are a class of molecules displaying biological activities in part

• chromatographical purification that was employed in the milligram-scale synthesis. Overall, this synthetic route is efficient and applicable to scale-up. Conclusion In summary, we have developed a facile and efficient strategy for the synthesis of 2-aminobenzothiopyranones through a conjugated addition–elimination

Low-budget 3D-printed equipment for continuous flow reactions

• Jochen M. Neumaier,
• Amiera Madani,
• Thomas Klein and
• Thomas Ziegler

Beilstein J. Org. Chem. 2019, 15, 558–566, doi:10.3762/bjoc.15.50

• like better mixing, more efficient heat transfer, and less scale-up problems [1]. For these reasons the number of publications in this field is rapidly increasing over the last decades. Another benefit of flow syntheses is the opportunity to perform multistep reactions with several reactors in a single

Asymmetric synthesis of a high added value chiral amine using immobilized ω-transaminases

• Antonella Petri,
• Valeria Colonna and
• Oreste Piccolo

Beilstein J. Org. Chem. 2019, 15, 60–66, doi:10.3762/bjoc.15.6

• on the substrate 1, no relevant changes in activity and selectivity were obtained. In order to optimize the reaction, some scale-up tests were performed using 200 mg of ATA-025-IMB and a substrate concentration of 40 g/L. Compared to the reactions carried out with smaller amounts of substrate, the

Assembly of fully substituted triazolochromenes via a novel multicomponent reaction or mechanochemical synthesis

• Robby Vroemans,
• Yenthel Verhaegen,
• My Tran Thi Dieu and
• Wim Dehaen

Beilstein J. Org. Chem. 2018, 14, 2689–2697, doi:10.3762/bjoc.14.246

• triazolochromene 5a and obtained oxidized side product 6. Reaction pathways leading to the different regioisomers. Synthesis of bis-chromenotriazole 5p. Scale-up of the one-pot three-component reaction and two-step ball milling procedure. Postfunctional transformations of triazolochromenes. Supporting Information

Quinolines from the cyclocondensation of isatoic anhydride with ethyl acetoacetate: preparation of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate and derivatives

• Nicholas G. Jentsch,
• Jared D. Hume,
• Emily B. Crull,
• Samer M. Beauti,
• Amy H. Pham,
• Julie A. Pigza,
• Jacques J. Kessl and
• Matthew G. Donahue

Beilstein J. Org. Chem. 2018, 14, 2529–2536, doi:10.3762/bjoc.14.229

• the benzene ring of the quinolone [13]. The known synthesis of quinoline core 8 has been published in a one-pot, two-step reaction from 4-bromoaniline (7) and diethyl acetylsuccinate in 36% yield (Scheme 2) [14][15]. However, our attempts to repeat and scale-up this procedure beyond a few hundred

• hydroxide [19][20]. The use of sodium hydride is of particular concern upon reaction scale-up due to limited solubility in organic solvents and the production of flammable hydrogen gas [21][22]. Sodium hydroxide avoids the off-gassing of hydrogen and produces water instead, thereby avoiding the use of any

A general and atom-efficient continuous-flow approach to prepare amines, amides and imines via reactive N-chloramines

• Katherine E. Jolley,
• Michael R. Chapman and
• A. John Blacker

Beilstein J. Org. Chem. 2018, 14, 2220–2228, doi:10.3762/bjoc.14.196

• upon scale-up makes this a useful reaction to translate to flow. Likewise, imines are an important class of compounds and are increasingly used as precursors to optically active amines [35][36][37][38][39]. Whilst normally prepared via a corresponding carbonyl compound, final dehydration can be