Continuous flow synthesis of azobenzenes via Baeyer–Mills reaction

• Jan H. Griwatz,
• Anne Kunz and
• Hermann A. Wegner

Beilstein J. Org. Chem. 2022, 18, 781–787, doi:10.3762/bjoc.18.78

• used Baeyer–Mills coupling reaction was adopted to a continuous flow setup. The versatility was demonstrated with a scope of 20 substances and the scalability of this method exemplified by the synthesis of >70 g of an azobenzene derivative applied in molecular solar thermal storage (MOST) systems

• . Keywords: azobenzenes; Baeyer–Mills reaction; continuous flow; molecular switches; solar fuel; Introduction Although the red-colored azobenzenes (AB) have been known for years as dyes, their applications nowadays span from energy and information storage [1][2][3][4][5], organocatalysis [6], photobiology

• the proposed mechanism, which involves nucleophilic attack of the aniline on the nitrosobenzene derivatives in acidic or basic media (Scheme 1) [18][19][20][21]. However, in order to use azobenzenes as functional materials, access to a large-scale process is necessary. In this context continuous flow

Synthesis of odorants in flow and their applications in perfumery

• Merlin Kleoff,
• Paul Kiler and
• Philipp Heretsch

Beilstein J. Org. Chem. 2022, 18, 754–768, doi:10.3762/bjoc.18.76

• , Germany 10.3762/bjoc.18.76 Abstract Continuous flow technology is a key technology for sustainable manufacturing with numerous applications for the synthesis of fine chemicals. In recent years, the preparation of odorants utilizing the advantages of flow reactors received growing attention. In this

• review, we give an overview of selected methods for the synthesis of odorants in flow, including heterogeneously catalyzed reactions, gas reactions, and photochemical C–H functionalization processes. After a brief introduction on types of odorants, the presented odorant syntheses are ordered according to

• the main odor families “fruity”, “green”, “marine”, “floral”, “spicy”, “woody”, “ambery”, and “musky” and their use and importance for perfumery is briefly discussed. Keywords: flow chemistry; fragrances; odorants; scents; terpenes; Introduction The history of odorants goes back to ancient cultures

Identification of the new prenyltransferase Ubi-297 from marine bacteria and elucidation of its substrate specificity

• Jamshid Amiri Moghaddam,
• Huijuan Guo,
• Karsten Willing,
• Thomas Wichard and
• Christine Beemelmanns

Beilstein J. Org. Chem. 2022, 18, 722–731, doi:10.3762/bjoc.18.72

• °C using a Luna Omega C18 column (100 × 2.1 mm, 1.6 μm, 100 Å, Phenomenex) preceded by a SecurityGuardTM ULTRA guard cartridge (2 × 2.1 mm, Phenomenex). Mobile phases were acidified with 0.1% formic acid and consisted of H2O (A), and acetonitrile (B) with a flow rate of 0.3 mL/min and the injection

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• chemistry, but also in medicine. Traditionally, inductive heating is used in industry, e.g., for heating large metallic objects including bending, bonding, and welding pipes. In addition, inductive heating has emerged as a partner for flow chemistry, both of which are enabling technologies for organic

• synthesis. This report reviews the combination of flow chemistry and inductive heating in industrial settings as well as academic research and demonstrates that the two technologies ideally complement each other. Keywords: catalysis; enabling technologies; flow chemistry; inductive heating; multistep

• applications under flow conditions 2.1 General remarks Energy efficiency is one of the most important cost factors in industrial processes, especially for high temperature reactions in fixed-bed reactors. In general, conductive particles or (superpara)magnetic nanoparticles are suitable as fixed-bed materials

Rapid gas–liquid reaction in flow. Continuous synthesis and production of cyclohexene oxide

• Kyoko Mandai,
• Tetsuya Yamamoto,
• Hiroki Mandai and
• Aiichiro Nagaki

Beilstein J. Org. Chem. 2022, 18, 660–668, doi:10.3762/bjoc.18.67

• Medical Science, Nijigaoka, Kani-city, Gifu Prefecture, 509-0293, Japan 10.3762/bjoc.18.67 Abstract The enhanced reaction rate in the epoxidation of cyclohexene with air as an oxidant was discovered without any added catalyst utilizing a continuous flow reactor constructed with readily available

• stainless steel parts and devices. This continuous-flow process demonstrates a significant improvement in reaction time for highly selective epoxide production over the batch process due to the efficient mass transfer between the liquid phase and air. The flow process discovered was operated continuously

• with good operational stability, evaluated by a constant high yield of cyclohexene oxide, to obtain the desired product with high productivity. Keywords: air; continuous flow; cyclohexene oxide; flow epoxidation; rapid gas–liquid reaction; Introduction From the past to the present, organic synthesis

Shift of the reaction equilibrium at high pressure in the continuous synthesis of neuraminic acid

• Jannis A. Reich,
• Miriam Aßmann,
• Kristin Hölting,
• Paul Bubenheim,
• Jürgen Kuballa and
• Andreas Liese

Beilstein J. Org. Chem. 2022, 18, 567–579, doi:10.3762/bjoc.18.59

• Abstract The importance of a compound that helps fight against influenza is, in times of a pandemic, self-evident. In order to produce these compounds in vast quantities, many researchers consider continuous flow reactors in chemical industry as next stepping stone for large scale production. For these

• recycling steps, and were characterized regarding the reaction kinetics (initial rate) and scalability (different lab scales) in a batch reactor. The reaction kinetics were studied in a continuous flow reactor. A high-pressure circular reactor (up to 130 MPa) was applied for the investigation of changes in

• the position of the equilibrium is to be investigated, high residence times and small flow rates are needed. Since the pressure drop across a capillary depends on the flow rate, it was not possible to build up sufficient pressure when investigating the equilibrium. For this reason, the fixed-bed

Terpenoids from Glechoma hederacea var. longituba and their biological activities

• Dong Hyun Kim,
• Song Lim Ham,
• Zahra Khan,
• Sun Yeou Kim,
• Sang Un Choi,
• Chung Sub Kim and
• Kang Ro Lee

Beilstein J. Org. Chem. 2022, 18, 555–566, doi:10.3762/bjoc.18.58

• . The monosaccharide of 5 was detected at 13.8 min, the same detection time (13.8 min) as ᴅ-glucopyranoside. LC–MS analysis was perfomed under the following conditions: flow rate 0.7 mL/min; 25% MeCN with 0.1% formic acid, column, Kinetex C18 column (250 mm × 4.6 mm, 5 µm, Phenomenex). Sugar analysis

• ) as ᴅ-glucopyranoside. GC–MS analysis was perfomed under the following conditions: capillary column, HP-5MS UI (30 m × 0.25 mm × 0.25 μm, Agilent); column temperature, 230 °C; injection temperature, 250 °C; flow rate, 1.0 mL/min; carrier gas, N2 [22]. Cytotoxic activity, NO production, NGF secretion

Synthesis of a new water-soluble hexacarboxylated tribenzotriquinacene derivative and its competitive host–guest interaction for drug delivery

• Man-Ping Li,
• Nan Yang and
• Wen-Rong Xu

Beilstein J. Org. Chem. 2022, 18, 539–548, doi:10.3762/bjoc.18.56

• 90% acetonitrile with 0.1% formic acid and 10% water with 0.1% formic acid at a flow rate of 0.4 mL/min. Freeze-drying was conducted on a Scientz-18N freeze-dryer. Synthesis of compound 2. A mixture of compound 1 (2.30 g, 3.7 mmol), ethyl azidoacetate (5.76 g, 44.7 mmol), copper(II) sulfate

Synthesis of 3,4,5-trisubstituted isoxazoles in water via a [3 + 2]-cycloaddition of nitrile oxides and 1,3-diketones, β-ketoesters, or β-ketoamides

• Md Imran Hossain,
• Md Imdadul H. Khan,
• Seong Jong Kim and
• Hoang V. Le

Beilstein J. Org. Chem. 2022, 18, 446–458, doi:10.3762/bjoc.18.47

• , Saugus, MA, USA). The DART ion source was operated with helium gas (approximately 4.0 L/min flow rate), the gas heater (350 °C), and the source grid (350 V). The data acquisition range was from m/z 50 to 1000. Polyethylene glycol (PEG 600) was used for the exact mass calibration. General synthetic

Cs₂CO₃-Promoted reaction of tertiary bromopropargylic alcohols and phenols in DMF: a novel approach to α-phenoxyketones

• Ol'ga G. Volostnykh,
• Olesya A. Shemyakina,
• Anton V. Stepanov and
• Igor' A. Ushakov

Beilstein J. Org. Chem. 2022, 18, 420–428, doi:10.3762/bjoc.18.44

• , thickness of stationary phase film 0.25 μm; injector temperature 250 °C, gas carrier – helium, flow rate 0.7 mL/min; detector temperature 250 °C; mass analyzer: quadrupole, electron ionization, electron energy: 70 eV, ion source temperature 200 °C; mass range 34–650 Da. The solvent was distilled DMF. Column

Four bioactive new steroids from the soft coral Lobophytum pauciflorum collected in South China Sea

• Di Zhang,
• Zhe Wang,
• Xiao Han,
• Xiao-Lei Li,
• Zhong-Yu Lu,
• Bei-Bei Dou,
• Wen-Ze Zhang,
• Xu-Li Tang,
• Ping-Lin Li and
• Guo-Qiang Li

Beilstein J. Org. Chem. 2022, 18, 374–380, doi:10.3762/bjoc.18.42

• -operation and Development (OECD). The zebrafish were maintained under a 14/10 h light/dark cycle at the temperature (28 ± 0.5°C) in a closed flow-through system with charcoal-filtered tap water to ensure normal spawning. CuSO4-induced model of zebrafish In a manner similar to literature reference [11

Amamistatins isolated from Nocardia altamirensis

• Till Steinmetz,
• Wolf Hiller and
• Markus Nett

Beilstein J. Org. Chem. 2022, 18, 360–367, doi:10.3762/bjoc.18.40

• supplemented with 0.1% (v/v) trifluoroacetic acid. The gradient conditions were as follows: from 40% methanol to 70% in 5 minutes followed by an increase to 90% in 20 minutes, kept at 90% for 10 minutes. The flow rate was set to 10 mL/min. The elution of compounds was monitored with a diode array detector

• . Again, CAS active fractions were collected. For the final purification step, a Nucleodur C18 Isis column (250 × 10 mm, 5 μm, Macherey-Nagel) was used with a linear gradient from 25% to 90% acetonitrile in water + 0.1% (v/v) trifluoroacetic acid over a period of 30 min. The flow rate was set to 6 mL/min

Synthesis of piperidine and pyrrolidine derivatives by electroreductive cyclization of imine with terminal dihaloalkanes in a flow microreactor

• Yuki Naito,
• Naoki Shida and
• Mahito Atobe

Beilstein J. Org. Chem. 2022, 18, 350–359, doi:10.3762/bjoc.18.39

• available imine and terminal dihaloalkanes in a flow microreactor. Reduction of the substrate imine on the cathode proceeded efficiently due to the large specific surface area of the microreactor. This method provided target compounds in good yields compared to a conventional batch-type reaction

• . Furthermore, piperidine and pyrrolidine derivatives could be obtained on preparative scale by continuous electrolysis for approximately 1 hour. Keywords: electrochemical synthesis; electrocyclization; flow microreactor; heterocyclic amines; imine; Introduction Heterocycles are a very important class of

• their demonstration. Therefore, it is desirable to conduct the reductive cyclizations without the use of a mercury cathode, and the development of a simple, green, and efficient method for the electrochemical synthesis of heterocyclic amines is an important research target. The electrochemical flow

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

• Kian Donnelly Marcus Baumann School of Chemistry, University College Dublin, Science Centre South, Belfield, Dublin 4, Ireland 10.3762/bjoc.18.27 Abstract An efficient continuous flow process is reported for the synthesis of various 1,3,4-oxadiazoles via an iodine-mediated oxidative cyclisation

• 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

• an integrated quenching and extraction step. Lastly, the use of an automated in-line chromatography system was exploited to realise a powerful flow platform for the generation of the heterocyclic targets. Keywords: chromatography; flow synthesis; in-line purification; oxadiazole; reaction

Organocatalytic asymmetric nitroso aldol reaction of α-substituted malonamates

• Ekta Gupta,
• Narendra Kumar Vaishanv,
• Sandeep Kumar,
• Raja Krishnan Purshottam,
• Ruchir Kant and
• Kishor Mohanan

Beilstein J. Org. Chem. 2022, 18, 217–224, doi:10.3762/bjoc.18.25

• /v, flow rate 1.0 mL/min, 254 nm, τminor = 13.0 min, τmajor = 13.9 min, 90% ee). HRMS (m/z): [M + Na]+ calcd for C17H17BrN2NaO4+, 415.0264; found, 415.0278. ORTEP diagram drawn with 30% ellipsoid probability for non-H atoms of the crystal structure of chiral compound 4a determined at 293 K. The

Anomeric 1,2,3-triazole-linked sialic acid derivatives show selective inhibition towards a bacterial neuraminidase over a trypanosome trans-sialidase

• Peterson de Andrade,
• Sanaz Ahmadipour and
• Robert A. Field

Beilstein J. Org. Chem. 2022, 18, 208–216, doi:10.3762/bjoc.18.24

• ). The organic layer was dried over MgSO4, filtered, concentrated under vacuum and purified by flash chromatography [cartridge: SNAP Ultra 10g; isocratic: 80–80% and 100–100% EtOAc/hexane (v:v); flow: 12 mL/min] to afford 1,4-disubstituted 1,2,3-triazole derivatives 2a–h in good yields and purity. After

Glycosylated coumarins, flavonoids, lignans and phenylpropanoids from Wikstroemia nutans and their biological activities

• Meifang Wu,
• Xiangdong Su,
• Yichuang Wu,
• Yuanjing Luo,
• Ying Guo and
• Yongbo Xue

Beilstein J. Org. Chem. 2022, 18, 200–207, doi:10.3762/bjoc.18.23

• ) at 35 °C with isocratic elution of 25% CH3CN in 0.1% H3PO4 for 40 min and subsequent washing of the column with 90% CH3CN at a flow rate 0.8 mL/min. Peaks at 16.54 and 19.64 min have coincided with derivatives of ᴅ-glucose and ᴅ-xylose [30]. Chemical structures of compounds 1–17 from W. nutans. The

High-speed C–H chlorination of ethylene carbonate using a new photoflow setup

• Takayoshi Kasakado,
• Takahide Fukuyama,
• Tomohiro Nakagawa,
• Shinji Taguchi and
• Ilhyong Ryu

Beilstein J. Org. Chem. 2022, 18, 152–158, doi:10.3762/bjoc.18.16

• ethylene carbonate was introduced to the reactor, the residence time was measured to be 15 or 30 s, depending on the slope of the reactor set at 15 or 5°, respectively. Such short time of exposition sufficed the photo C–H chlorination. The partial irradiation of the flow channels also sufficed for the C–H

• ; ethylene carbonate; photo flow reactor; vinylene carbonate; Introduction The C–H chlorination by molecular chlorine is a highly exothermic reaction that proceeds via a radical chain mechanism as illustrated in Scheme 1 [1][2][3][4][5][6]. Frequently, photoirradiation is used for radical initiation through

• , sustaining the radical chain. Chlorine gas is a cheap feedstock since it is formed as a byproduct of the electrolysis of NaCl to produce NaOH in an industrial process [7]. We felt that C–H chlorination would be updated by using scalable flash chemistry [8]. Flow C–H chlorination using a compact flow reactor

Tenacibactins K–M, cytotoxic siderophores from a coral-associated gliding bacterium of the genus Tenacibaculum

• Yasuhiro Igarashi,
• Yiwei Ge,
• Tao Zhou,
• Amit Raj Sharma,
• Enjuro Harunari,
• Naoya Oku and
• Agus Trianto

Beilstein J. Org. Chem. 2022, 18, 110–119, doi:10.3762/bjoc.18.12

• Cholester Packed Column, 10 × 250 mm, Nacalai Tesque) using an isocratic elution with 50% MeCN in 0.1% HCO2H over 40 min at a flow rate of 4 mL/min, yielding tenacibactin K (1, 31.6 mg, tR 28.0 min), tenacibactin L (2, 2.8 mg, tR 22.0 min), and tenacibactin M (3, 18.2 mg, tR 34.4 min). Tenacibactin K (1

Regioselective synthesis of methyl 5-(N-Boc-cycloaminyl)-1,2-oxazole-4-carboxylates as new amino acid-like building blocks

• Jolita Bruzgulienė,
• Greta Račkauskienė,
• Aurimas Bieliauskas,
• Vaida Milišiūnaitė,
• Miglė Dagilienė,
• Gita Matulevičiūtė,
• Vytas Martynaitis,
• Sonata Krikštolaitytė,
• Frank A. Sløk and
• Algirdas Šačkus

Beilstein J. Org. Chem. 2022, 18, 102–109, doi:10.3762/bjoc.18.11

• /(H2O + 0.1% HCOOH (30:70 isocratic mode); T = 36 °C; flow rate 1.0 mL/min. Samples were prepared in methanol. The injection volume was 10 μL, λdet = 245 nm. (a) Structure of 4b with syn- and anti-conformers; (b) superimposed 1H NMR and 1D gradient NOE spectra with a selective irradiation of signal at δ

1,2-Naphthoquinone-4-sulfonic acid salts in organic synthesis

• Ruan Carlos B. Ribeiro,
• Patricia G. Ferreira,
• Amanda de A. Borges,
• Luana da S. M. Forezi,
• Fernando de Carvalho da Silva and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 53–69, doi:10.3762/bjoc.18.5

• addition, several authors concluded that this was a good method for analytically determining low levels of activated aromatic amines in drugs. This method continued to be used over the years and was subsequently optimized by a spectrophotometric determination technique coupled with continuous flow [55]. In

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

• strategy. Proposed mechanistic pathway for the cyanation of the aldimine intermediate. Strecker-type functionalization of N-aryl-substituted tetrahydroisoquinolines under flow conditions. One-pot synthesis of α-aminonitriles using RuCl3 as catalyst. Synthesis of alkyl nitriles using (Ru(TMHD)3) as the

First total synthesis of hoshinoamide A

• Haipin Zhou,
• Zihan Rui,
• Yiming Yang,
• Shengtao Xu,
• Yutian Shao and
• Long Liu

Beilstein J. Org. Chem. 2021, 17, 2924–2931, doi:10.3762/bjoc.17.201

• % CH3CN/H2O and 0.1% TFA over 40 min were applied at a flow rate of 1.0 mL/min and detection at 220 nm. Method B: Linear gradient of 10–90–90–10% CH3CN/H2O and 0.1% TFA over 10 min (10–90 vol % MeCN over 6 min, 90–90 vol % over 3 min, 90–10 vol % MeCN over 1 min) were applied at a flow rate of 1.0 mL/min

• –90 vol % MeCN over 30 min, 90–90 vol % over 10 min, 90–10 vol % MeCN over 10 min) at a flow rate of 8 mL/min. Standard SPPS (solid-phase peptide synthesis) method: General procedures for coupling on resin: The loaded resin was shaken for 2 h at room temperature with a solution of the desired Fmoc-AA

The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet–Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids

• Marco Keller,
• Karl Sauvageot-Witzku,
• Franz Geisslinger,
• Nicole Urban,
• Michael Schaefer,
• Karin Bartel and
• Franz Bracher

Beilstein J. Org. Chem. 2021, 17, 2716–2725, doi:10.3762/bjoc.17.183

• compounds 2a–f, 3a–c and 4 regarding their P-glycoprotein blocking potential. For that, we used the P-glycoprotein substrate calcein as reporter dye and analyzed intracellular calcein fluorescence of P-glycoprotein overexpressing VCR-R CEM cells by flow cytometry. An increase of the calcein-positive

• after substraction of the basal value. Flow cytometry P-glycoprotein activity was assessed using the reporter dye calcein acetoxymethyl ester (AM) as described previously [59]. To assess apoptosis, VCR-R CEM cells were seeded at 0.125 × 106 cells/well, incubated for 4 h and stimulated as indicated for

• 48 h. Apoptosis was analyzed by propidium iodide staining and flow cytometry as described by Nicoletti et al. [60]. All flow cytometry experiments were conducted on a BD FACS Canto II (BD Biosciences). Prominent synthetic approaches to 1-benzyltetrahydroisoquinolines: Bischler–Napieralski, Pictet

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

• terminal alkynes has been achieved in a continuous-flow microreactor through 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)/copper relay catalysis. The reaction is easily scalable and requires low concentration of supporting electrolyte and no external chemical oxidants or ligands, providing straightforward

• and sustainable access to 2-functionalized tetrahydroisoquinolines. Keywords: continuous flow; copper; catalysis; dehydrogenative cross-coupling; electrochemistry; Introduction The dehydrogenative cross-coupling of two C–H bonds represents an ideal strategy for the construction of C–C bonds [1][2

• reaction of tetrahydroisoquinolines with terminal alkynes (Scheme 1C) [10]. The chiral ligand was found to be critical for the stereoinduction as well as product formation for these electrochemical reactions that are conducted in batch. Continuous-flow electrochemical microreactors offer several advantages