An alternative C–P cross-coupling route for the synthesis of novel V-shaped aryldiphosphonic acids

• Stephen J. I. Shearan,
• Enrico Andreoli and
• Marco Taddei

Beilstein J. Org. Chem. 2022, 18, 1518–1523, doi:10.3762/bjoc.18.160

• of us, was limited to 0.543 g (1 mmol) of substrate. Scale up of this protocol was not attempted, but it might become problematic due to issues with microwave penetration in a medium that contains a strong absorber, such as the Ni catalytic complex. In this work, we have employed either 5.0 g (15.3

A one-pot electrochemical synthesis of 2-aminothiazoles from active methylene ketones and thioureas mediated by NH₄I

• Shang-Feng Yang,
• Pei Li,
• Zi-Lin Fang,
• Sen Liang,
• Hong-Yu Tian,
• Bao-Guo Sun,
• Kun Xu and
• Cheng-Chu Zeng

Beilstein J. Org. Chem. 2022, 18, 1249–1255, doi:10.3762/bjoc.18.130

• . To demonstrate the practicability of the reaction, a scale-up reaction of ethyl acetoacetate (1a, 28 mmol, 3.64 g) and thiourea (2a,14 mmol, 1.05 g) was carried out under the optimized conditions to give 3a in 50% yield (Scheme 3). In order to better understand the iodide-mediated reaction mechanism

Electro-conversion of cumene into acetophenone using boron-doped diamond electrodes

• Mana Kitano,
• Tsuyoshi Saitoh,
• Shigeru Nishiyama,
• Yasuaki Einaga and
• Takashi Yamamoto

Beilstein J. Org. Chem. 2022, 18, 1154–1158, doi:10.3762/bjoc.18.119

• , where the BDD’s wide potential window enables the direct anodic oxidation of cumene into the cumyl cation. Since electricity is directly employed as the oxidizing and reducing reagents, the present protocol is easy to use, suitable for scale-up, and inherently safe. Keywords: aromatic alkyl; boron

Electrogenerated base-promoted cyclopropanation using alkyl 2-chloroacetates

• Kouichi Matsumoto,
• Yuta Hayashi,
• Kengo Hamasaki,
• Mizuki Matsuse,
• Hiyono Suzuki,
• Keiji Nishiwaki and
• Norihito Kawashita

Beilstein J. Org. Chem. 2022, 18, 1116–1122, doi:10.3762/bjoc.18.114

• -chloroacetates in Bu4NBr/DMF using a divided cell equipped with Pt electrodes to produce the corresponding cyclopropane derivatives in moderate yields were discovered. The reaction conditions were optimized, the scope and limitations, as well as scale-up reactions were investigated. The presented method for the

• -chloroacetates to cyclopropane derivatives has been developed. The reaction has been optimized, the scope and limitations have been investigated. Scale-up reactions were performed and satisfactory yields obtained. The generation of an EGB of the enolate ion from alkyl 2-chloroacetates is indicated. The current

• cyclopropanetricarboxylates. Previous reports (reactions 1–3) and this work (reaction 4). Plausible reaction mechanism. EGB = electrogenerated base. Reaction optimization. Effect of electricity around 1 F/mol and type of electrochemical cell. Scope and limitations. Scale-up experiments. Supporting Information Supporting

Automated grindstone chemistry: a simple and facile way for PEG-assisted stoichiometry-controlled halogenation of phenols and anilines using N-halosuccinimides

• Dharmendra Das,
• Akhil A. Bhosle,
• Amrita Chatterjee and
• Mainak Banerjee

Beilstein J. Org. Chem. 2022, 18, 999–1008, doi:10.3762/bjoc.18.100

• ortho- and para-positions. The gram-scale reaction shows similar efficiency like smaller batches indicating easy scale-up of this protocol. The method is environmentally friendly and cost-effective having key attributes like simple instrumentation, no aqueous workup, short reaction time, and mild

First example of organocatalysis by cathodic N-heterocyclic carbene generation and accumulation using a divided electrochemical flow cell

• Daniele Rocco,
• Ana A. Folgueiras-Amador,
• Richard C. D. Brown and
• Marta Feroci

Beilstein J. Org. Chem. 2022, 18, 979–990, doi:10.3762/bjoc.18.98

• technique. Again, productivity for the esterification is four-fold higher (3.65 mmol/h, 0.1 M solution) in flow than in batch (0.97 mmol/h, pure IL), and in flow the reaction volume could simply be increased to allow scale-up, obviously in a longer time. Conclusion The results reported in this work

• scale up. In the case of the flow procedure, a 0.1 M solution of the IL is employed, which may be more convenient than using pure ILs. Further investigations of electrogeneration of NHCs and applications in organic synthesis are underway. Experimental Materials and methods Chemicals were purchased from

Synthesis of α-(perfluoroalkylsulfonyl)propiophenones: a new set of reagents for the light-mediated perfluoroalkylation of aromatics

• Durbis J. Castillo-Pazos,
• Juan D. Lasso and
• Chao-Jun Li

Beilstein J. Org. Chem. 2022, 18, 788–795, doi:10.3762/bjoc.18.79

• perfluoroalkylating reagent that participated in such condensation (around 30%), giving us the final yields of perfluoroalkylating reagents 1a–c displayed in Scheme 3. Afterward, to show the practicality of application of these reagents in industry, we proceeded to scale up their synthesis in gram-scale

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