New synthesis of a late-stage tetracyclic key intermediate of lumateperone

• Mátyás Milen,
• Bálint Nyulasi,
• Tamás Nagy,
• Gyula Simig and
• Balázs Volk

Beilstein J. Org. Chem. 2022, 18, 653–659, doi:10.3762/bjoc.18.66

• require a reduction step carried out with borane·THF complex that is used in the syntheses described in the literature but would make it difficult to scale up the process. The significance of compound (±)-9a lies in the fact that it can be converted in a known one-step reaction to compound (±)-10. The

The asymmetric Henry reaction as synthetic tool for the preparation of the drugs linezolid and rivaroxaban

• Martin Vrbický,
• Karel Macek,
• Jaroslav Pochobradský,
• Jan Svoboda,
• Miloš Sedlák and
• Pavel Drabina

Beilstein J. Org. Chem. 2022, 18, 438–445, doi:10.3762/bjoc.18.46

• epimers by recrystallization was tested. For this purpose, the nitroaldols 24 and 26 were prepared at a 10 mmol scale (ca. 4 g) using 10 mol % of the catalyst Cu(OAc)2/IV at 20 °C to achieve high yields of the products (24: 92% and 26: 84%). The nitroaldols 24 and 26 were obtained in these scale-up

Flow synthesis of oxadiazoles coupled with sequential in-line extraction and chromatography

• Kian Donnelly and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 232–239, doi:10.3762/bjoc.18.27

• approach. This entails the use of a heated packed-bed reactor filled with solid K2CO3 as a base. Using DMSO as solvent, this flow method generates the target heterocycles within short residence times of 10 minutes and in yields up to 93%. Scale-up of this flow process was achieved (34 mmol/h) and featured

• , without the need for further extensive optimisation. Oxadiazole product 2j was chosen as the target molecule for the scale-up reaction due to the potential for further diversification via the embedded alkene. Due to the large quantity of material, an increase in column size was required to house the

• of complex oxadiazoles. Continuous flow scale-up reaction with in-line quench and extraction. Continuous flow setup equipped with in-line extraction and purification. Screening of oxidants for cyclisation of acyl hydrazone. Optimisation of iodine-mediated cyclisation in continuous flow mode

Recent advances and perspectives in ruthenium-catalyzed cyanation reactions

• Thaipparambil Aneeja,
• Cheriya Mukkolakkal Abdulla Afsina,
• Padinjare Veetil Saranya and
• Gopinathan Anilkumar

Beilstein J. Org. Chem. 2022, 18, 37–52, doi:10.3762/bjoc.18.4

• proposed mechanism for the cyanation step is depicted in Scheme 21. Chemical synthesis usually needs labor-intensive and tiresome procedures. One of the approaches to overcome these challenges is to perform the reactions in flow [44]. The major advantages of this approach include predictable reaction scale

• -up, high reproducibility and yields, lower catalyst loading, high product purity, and excellent selectivity. A visible-light-promoted Strecker-type functionalization of N-aryl-substituted tetrahydroisoquinolines under flow conditions was reported (Scheme 22) [45]. The cyanating agent utilized was

A two-phase bromination process using tetraalkylammonium hydroxide for the practical synthesis of α-bromolactones from lactones

• Yuki Yamamoto,
• Akihiro Tabuchi,
• Kazumi Hosono,
• Takanori Ochi,
• Kento Yamazaki,
• Shintaro Kodama,
• Akihiro Nomoto and
• Akiya Ogawa

Beilstein J. Org. Chem. 2021, 17, 2906–2914, doi:10.3762/bjoc.17.198

• reaction with bromine (Scheme 1a) [37][38]. While the industrial demand for α-bromolactones has grown in recent years, the above-mentioned laboratory-level synthetic methods are not suitable for scale-up because LDA, TMSCl, and enol silyl ethers are sensitive to moisture and air, as well as being expensive

• , with synthesis scale-up tolerated under mild conditions. To facilitate the construction of various functional scaffolds using this system, lactones were subsequently α-functionalized via the corresponding α-bromolactones using this two-phase system. Interestingly, 3b synthesized using this method was

Electrocatalytic C(sp³)–H/C(sp)–H cross-coupling in continuous flow through TEMPO/copper relay catalysis

• Bin Guo and
• Hai-Chao Xu

Beilstein J. Org. Chem. 2021, 17, 2650–2656, doi:10.3762/bjoc.17.178

• for electrosynthesis and have been employed to reduce the use of supporting electrolyte, facilitate reaction scale-up, and increase reaction efficiency [20][21][22][23][24][25][26][27][28][29][30][31][32]. Despite these advantages of continuous-flow electrosynthesis and the intense interests in

• scale-up. Proposed mechanism. Optimization of reaction conditions.a Supporting Information Supporting Information File 372: General procedure, characterization data for electrolysis products and NMR spectra. Funding Financial support of this research from NSFC (21971213) and the Fundamental Research

A visible-light-induced, metal-free bis-arylation of 2,5-dichlorobenzoquinone

• Pieterjan Winant and
• Wim Dehaen

Beilstein J. Org. Chem. 2021, 17, 2315–2320, doi:10.3762/bjoc.17.149

• ortho-substituent, 3o was successfully synthesized in a yield comparable to its para-substituted analog 3a. The brominated product 3p, however, proved to be unstable. The inability to scale-up Meerwein-type arylations is a flaw often ascribed to the explosive nature of the aryldiazonium salts. Since the

• product. The reactive aryldiazonium salt is synthesized in situ, minimizing risks and enabling scale-up. The chlorine substituents on the quinone were successfully functionalized as part of the synthesis of natural product betulinan A, proving that this work may further facilitate the synthesis of new

A recent overview on the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

• Pezhman Shiri,
• Ali Mohammad Amani and
• Thomas Mayer-Gall

Beilstein J. Org. Chem. 2021, 17, 1600–1628, doi:10.3762/bjoc.17.114

• addition, a range of functional groups have been investigated, and the results exhibited that they were unaffected. Finally, it would be possible to scale up the reaction with a negligible decrease in the yield of product [43]. The synthesis of enantiomerically pure 1,4,5-trisubstituted 1,2,3-triazoles 34

Iodine-catalyzed electrophilic substitution of indoles: Synthesis of (un)symmetrical diindolylmethanes with a quaternary carbon center

• Thanigaimalai Pillaiyar,
• Masoud Sedaghati,
• Andhika B. Mahardhika,
• Lukas L. Wendt and
• Christa E. Müller

Beilstein J. Org. Chem. 2021, 17, 1464–1475, doi:10.3762/bjoc.17.102

• employing indoles bearing bulky substituents at their 2-position (Ling et al.), or the need for chlorinated solvents (Sasaki et al.), as well as difficulty to scale up the reactions to a multigram scale, as well as a generally rather limited substrate scope. Therefore, finding a robust method with a broad

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• flow reacting acetone with a wide range of aldehydes. In batch, acetone-based aldol reactions are typically performed under biphasic conditions by slow addition of the aldehyde to an acetone/NaOH mixture kept at low temperatures. Upon scale-up, this carries with it problems such as inefficient mixing

• scale-up equating to prolonged run times. As a result, alternative support formats have been investigated. In this context there has been a growing interest in the use of functionalised hollow fibres including their application as membranes for gas separation [110] (e.g., CO2 absorption [111]) as they

• flow was also patented in 2014 by Strutz et al. [117]. Microinnova Engineering has devised a mesofluidic platform for continuous aldol reactions used in the synthesis of nabumetone (77) and other 4-aryl-2-butanone derivatives demonstrating the ease of scale-up associated with such transformations in

Heterogeneous photocatalytic cyanomethylarylation of alkenes with acetonitrile: synthesis of diverse nitrogenous heterocyclic compounds

• Guanglong Pan,
• Qian Yang,
• Wentao Wang,
• Yurong Tang and
• Yunfei Cai

Beilstein J. Org. Chem. 2021, 17, 1171–1180, doi:10.3762/bjoc.17.89

• naphthalene, the reaction successfully provided the benzoindoline 3g in 56% yield. Substrates with an N-Boc group also worked well to deliver the corresponding indoline 3h in 77% yield. Moreover, a scale-up reaction of 1a (2 mmol) was conducted, affording the corresponding product 3a (0.28 g) in a yield of 62

Recent advances in palladium-catalysed asymmetric 1,4–additions of arylboronic acids to conjugated enones and chromones

• Jan Bartáček,
• Jan Svoboda,
• Martin Kocúrik,
• Jaroslav Pochobradský,
• Alexander Čegan,
• Miloš Sedlák and
• Jiří Váňa

Beilstein J. Org. Chem. 2021, 17, 1048–1085, doi:10.3762/bjoc.17.84

• in its increased solubility. The impact of the addition of 30 mol % NH4PF6 caused that the product yield was almost doubled even when the temperature was 20 °C lower (Table 19) [48], while there was only a minimal to no effect on the enantioselectivity (Table 19). Scale-up to a gram-scale was

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• , multimode microwave reactors for parallel synthesis and multimode microwave reactors for single-batch scale-up. The reactors vary in capacity and the distribution mode of the electromagnetic wave in the reactor vessel. The introduction of the Si–C (silicon–carbon) vials enables high temperature resistance

• and selective heating of the heterogeneous catalyst [20][21][22][23]. Even though the MWA technology is advantageous, a major challenge posed is the scale-up at the industry level where protocol efficiency at kilogram scale is mandatory. With rapid heat generation, and litres of solvents often safety

• seems to be compromised imposing restrictions on using microwaves at a scale-up level. However, the batch process and continuous flow process seem to provide an entry into scale-up standards with safety. The microwave reactors serving the purpose of batch and parallel approach are designed in various

A chromatography-free and aqueous waste-free process for thioamide preparation with Lawesson’s reagent

• Ke Wu,
• Yichen Ling,
• An Ding,
• Liqun Jin,
• Nan Sun,
• Baoxiang Hu,
• Zhenlu Shen and
• Xinquan Hu

Beilstein J. Org. Chem. 2021, 17, 805–812, doi:10.3762/bjoc.17.69

• generate P-containing aqueous waste, and only organic effluents were discharged. It is believed that the optimized procedure offers the great opportunity of applying the Lawesson’s reagent for various thio-substitution reactions on a large scale. Keywords: chromatography-free; Lawesson’s reagent; scale-up

Valorisation of plastic waste via metal-catalysed depolymerisation

• Francesca Liguori,
• Carmen Moreno-Marrodán and
• Pierluigi Barbaro

Beilstein J. Org. Chem. 2021, 17, 589–621, doi:10.3762/bjoc.17.53

• to lactic acid units) and 1,4-dioxane solvent at 140 °C and 100 bar H2. A TOF of 6.19 molPD⋅molRu−1⋅h−1 can be calculated based on this. Scale-up using PLA granulates and beverage cups was also possible using a lower catalyst loading. In addition, the method allowed for the selective recycle of

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