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

Adjusting the length of supramolecular polymer bottlebrushes by top-down approaches

• Tobias Klein,
• Franka V. Gruschwitz,
• Maren T. Kuchenbrod,
• Ivo Nischang,
• Stephanie Hoeppener and
• Johannes C. Brendel

Beilstein J. Org. Chem. 2021, 17, 2621–2628, doi:10.3762/bjoc.17.175

• ][27][28]. Both methods are applied for fragmentation of initially µm-long SPBs based on BTU–PEO and BTP–PEO conjugates. The resulting nanofibers were characterized in detail by cryogenic transmission electron microscopy (cryoTEM), as well as by asymmetrical flow field-flow fractionation measurements

In-depth characterization of self-healing polymers based on π–π interactions

• Josefine Meurer,
• Julian Hniopek,
• Johannes Ahner,
• Michael Schmitt,
• Jürgen Popp,
• Stefan Zechel,
• Kalina Peneva and
• Martin D. Hager

Beilstein J. Org. Chem. 2021, 17, 2496–2504, doi:10.3762/bjoc.17.166

• ]. Besides the examples of self-healing/regeneration that exist in Nature, the general concept could also be transferred to different synthetic materials. Hereby, two concepts can be distinguished. In extrinsic self-healing materials, a material flow is achieved by the encapsulation of microcapsules [7] or

• flow behavior was started (see results of DMTA). Hereby, a partial healing was also observed (healing efficiency 50.64%, for pictures see Supporting Information File 1). Looking closer at the 3D-profiles, it can be seen that the depth of the scratch was reduced by more than 60% (from max. 64 µm to max

Isolation and characterization of new phenolic siderophores with antimicrobial properties from Pseudomonas sp. UIAU-6B

• Emmanuel T. Oluwabusola,
• Olusoji O. Adebisi,
• Fernando Reyes,
• Kojo S. Acquah,
• Mercedes De La Cruz,
• Larry L. Mweetwa,
• Joy E. Rajakulendran,
• Digby F. Warner,
• Deng Hai,
• Rainer Ebel and
• Marcel Jaspars

Beilstein J. Org. Chem. 2021, 17, 2390–2398, doi:10.3762/bjoc.17.156

• 20 min followed by a linear gradient from 20% to 50% MeOH over 10 min, 50% MeOH for 5 min, 50% to 70% MeOH/H2O for 15 min, 70% MeOH for 5 min, 70% to 100% MeOH/H2O for 15 min and 100% MeOH over 20 min) at a flow rate of 10 mL/min. Four fractions were obtained: FD1 (0.8 g, tR 8.2–12.0 min), FD2 (0.35

• g, tR 27–40 min), FD3 (0.24 g, tR 41–57 min), and FD4 (0.45 g, tR 58–70 min). Fraction FD1 (0.8 g) was subjected to reversed-phase semipreparative HPLC on a Sunfire column C18 (5 µm, 10 × 250 mm) with a linear gradient of H2O/MeOH 80–20% over 30 min at a flow rate of 2 mL/min, yielding compounds 7

• (5 µm, 10 × 250 mm) with a mobile phase gradient system of H2O/MeOH 80–20% and 0.01% TFA for 35 min at a flow rate of 2 mL/min to afford compound 2 (15.3 mg, tR 19.1 min). The final dichloromethane subfraction FD4 (0.45 g) was rechromatographed by reversed-phase HPLC using a Sunfire column C18 (5 µm

Photoredox catalysis in nickel-catalyzed C–H functionalization

• Lusina Mantry,
• Rajaram Maayuri,
• Vikash Kumar and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2021, 17, 2209–2259, doi:10.3762/bjoc.17.143

• process in a continuous-flow reactor. The mechanistic studies indicated that a nickel hydride intermediate generated with C(sp3)–H as the hydride source is involved in this catalytic transformation. The hydronickelation step results in the sterically less hindered vinylnickel intermediate 15-I, which

An initiator- and catalyst-free hydrogel coating process for 3D printed medical-grade poly(ε-caprolactone)

• Jochen Löblein,
• Thomas Lorson,
• Miriam Komma,
• Tobias Kielholz,
• Maike Windbergs,
• Paul D. Dalton and
• Robert Luxenhofer

Beilstein J. Org. Chem. 2021, 17, 2095–2101, doi:10.3762/bjoc.17.136

• polymerization should be feasible. At this point, the coating of the fibrous scaffolds is rather inhomogeneous, as the surface-initiated polymerization is confounded by polymerization in bulk. Therefore, we are currently working on a slightly modified experimental setup, which utilizes a flow setup, constantly

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• are crucial. In 2018, Ackermann and co-workers described a novel room temperature C–H arylation by using a continuous visible light photo-flow technique, allied with a manganese photocatalyst CpMn(CO)3 [142]. The new flow protocol enabled the synthesis of several arene- and heterocyclic-based

• compounds in excellent yields and short reaction times (Scheme 21B and C). The robustness of the manganese-catalyzed photo-flow reaction was demonstrated by a gram-scale preparation of the key intermediate in the synthesis of the pharmaceutical compound dantrolene (60) in high yields (Scheme 21D). The azide

Volatile emission and biosynthesis in endophytic fungi colonizing black poplar leaves

• Christin Walther,
• Pamela Baumann,
• Katrin Luck,
• Beate Rothe,
• Peter H. W. Biedermann,
• Jonathan Gershenzon,
• Tobias G. Köllner and
• Sybille B. Unsicker

Beilstein J. Org. Chem. 2021, 17, 1698–1711, doi:10.3762/bjoc.17.118

• PDMS tube from each replicate was placed in a glass tube (Supelco; Sigma-Aldrich). Desorption was achieved by a He flow (60 mL min−1) at 200 °C for 8 min in the glass tube and the analytes were trapped on a Tenax® (Buchem BV, Apeldoorn, Netherlands) adsorbent trap at −17 °C. The trap was then heated to

• 230 °C, and the analytes injected onto the GC column (Rtx®-5MScolumn with 30 m × 0.25 mm × 0.25 μm (Restek GmbH, Bad Homburg, Germany)). The gas chromatograph was operated at a column flow rate of 1.5 mL/min (He), split injection (split ratio: 5). The oven was set to 45 °C, held for 3 min, increased

• flow desalting column (GE Healthcare, Chicago, IL, USA) and eluted in extraction buffer. Enzyme assays were performed in a Teflon-sealed, screw-capped 1 mL GC glass vial containing 50 μL of the heterologously expressed protein and 50 µL assay buffer containing 50 μM substrate (GPP, (E,E)-FPP, or (E,E,E

Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

Analogs of the carotane antibiotic fulvoferruginin from submerged cultures of a Thai Marasmius sp.

• Birthe Sandargo,
• Leon Kaysan,
• Rémy B. Teponno,
• Christian Richter,
• Benjarong Thongbai,
• Frank Surup and
• Marc Stadler

Beilstein J. Org. Chem. 2021, 17, 1385–1391, doi:10.3762/bjoc.17.97

• min, flow rate: 0.6 mL/min, UV detection 200–600 nm, was used to obtain the HRESIMS data. NMR spectra were acquired on a Bruker Avance III 700 MHz spectrometer (Bremen, Germany) equipped with a 5 mm TCI cryoprobe (1H NMR (700 MHz), 13C NMR (175 MHz)). Optical rotations of the metabolites were measured

• % FA served as mobile phase, running a gradient of 10 min at 5% acetonitrile + 0.1% FA, then increasing to 100% within 70 min, flow rate: 40 mL/min, UV detection at 200–600 nm. Pre-fractions were further separated using a Luna C18(2) 250 × 21 mm, 7 μm column (Phenomenex, Aschaffenburg, Germany) and

• deionized water + 0.05% TFA (solvent A) and acetonitrile + 0.05% TFA (solvent B) as mobile phase and a flow rate of 18 mL/min. Gradients were established individually for each pre-fraction as follows: a pre-fraction at 36 to 37 minutes was further separated with a gradient of 20–50% solvent B within 60

A new glance at the chemosphere of macroalgal–bacterial interactions: In situ profiling of metabolites in symbiosis by mass spectrometry

• Marine Vallet,
• Filip Kaftan,
• Veit Grabe,
• Fatemeh Ghaderiardakani,
• Simona Fenizia,
• Aleš Svatoš,
• Georg Pohnert and
• Thomas Wichard

Beilstein J. Org. Chem. 2021, 17, 1313–1322, doi:10.3762/bjoc.17.91

• SunChrom MALDI spotter (SunChrom GmbH, Germany). The spraying method was optimised using the following parameters: line distance 2 mm, spraying speed 800 mm min−1 with 5 seconds drying time, and matrix solution flow rate in 4 cycles from 10 μL up to 30 μL min−1. Solvents used in this study were all LCMS

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

• temperatures, fragrance ingredients/intermediates make ideal candidates for continuous-flow manufacturing. This review highlights the potential crossover between a multibillion dollar industry and the flourishing sub-field of flow chemistry evolving within the discipline of organic synthesis. This is

• illustrated through selected examples of industrially important transformations specific to the fragrances and flavours industry and by highlighting the advantages of conducting these transformations by using a flow approach. This review is designed to be a compendium of techniques and apparatus already

• published in the chemical and engineering literature which would constitute a known solution or inspiration for commonly encountered procedures in the manufacture of fragrance and flavour chemicals. Keywords: flavours and fragrances; flow chemistry; process chemistry; synthesis; Introduction The fragrance

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• was the only effective reagent when performing the reaction at 60 °C in THF [16]. Ketimines were also synthesized with Ti(OEt)4, under microwave irradiation in a solvent-free system [20]. In hindered ketones, Ti(OiPr)4 or Ti(OEt)4 using vacuum or under a nitrogen flow were effective to tert

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

• , continuous-flow reactions are currently a general challenge, especially for the pharmaceutical industry. The prerequisite for a successful continuous synthesis in the field of asymmetric addition reactions to enones is the mastery of recyclable heterogeneous catalysis. Very recently, we reported [57] the

• first heterogeneous polystyrene-supported recyclable catalyst for asymmetric conjugate addition reactions of arylboronic acids to five and six-membered enones. In our laboratory, we also attempted to perform this reaction under flow conditions. However, the change from batch to flow arrangement itself

• is another challenging task. Nevertheless, it should be noted at this point that in the case of rhodium complex catalysis, the asymmetric addition of phenylboronic acid to enones in continuous flow has been successful [24]. In 2021, Walhers et al. presented a theoretical study based on the Q2MM

Synthesis of 10-O-aryl-substituted berberine derivatives by Chan–Evans–Lam coupling and investigation of their DNA-binding properties

• Peter Jonas Wickhorst,
• Mathilda Blachnik,
• Denisa Lagumdzija and
• Heiko Ihmels

Beilstein J. Org. Chem. 2021, 17, 991–1000, doi:10.3762/bjoc.17.81

• 5a–e in the presence of ct DNA were examined with flow linear dichroism (LD) and circular dichroism (CD) spectroscopy (Figure 5, Figure S6, Supporting Information File 1). The binding of ligands 5a–e resulted in the development of negative LD signals at 350–355 nm and 420–429 nm clearly indicating an

• dichroism (LD): Chirascan CD spectrometer, Applied Photophysics. Flow-LD: High Shear Cuvette Cell Accessory (Applied Photophysics); the LD samples were recorded in a rotating cuvette with a shear gradient of 1200 s−1. Melting points: Büchi 545 (Büchi, Flawil, CH). Materials Berberrubine (1b) was synthesized

Enhanced target cell specificity and uptake of lipid nanoparticles using RNA aptamers and peptides

• Roslyn M. Ray,
• Anders Højgaard Hansen,
• Maria Taskova,
• Bernhard Jandl,
• Jonas Hansen,
• Citra Soemardy,
• Kevin V. Morris and
• Kira Astakhova

Beilstein J. Org. Chem. 2021, 17, 891–907, doi:10.3762/bjoc.17.75

• was reduced under nitrogen flow. The received solid product was dissolved in DCM and subsequently reduced under nitrogen flow. This procedure was repeated two more times, followed by a lyophilization step to receive the crude peptide. The crude T7–lipid conjugate was purified by normal-phase

• was used to detect the LNPs, with a slide shutter level set to 1232 and the slider gain set to 219, and the syringe pump speed set to 30 using a flow-cell top plate module. Cell lines and maintenance HeLa and HEK293T cells were purchased from American Type Culture Collection (ATCC, VA). TZM-bls were

• h later, the apical layer was removed, and the basolateral cells were washed, trypsinized, and resuspended in 1× PBS. Detection of Cy5 was measured by flow cytometry on a BD Accuri™ C6 device (Becton, Dickinson and Company, NJ), and the data was analyzed using FlowJo™ Version 10.7.1 (Becton

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

• 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

Synthetic reactions driven by electron-donor–acceptor (EDA) complexes

• Zhonglie Yang,
• Yutong Liu,
• Kun Cao,
• Xiaobin Zhang,
• Hezhong Jiang and
• Jiahong Li

Beilstein J. Org. Chem. 2021, 17, 771–799, doi:10.3762/bjoc.17.67

• the secondary amine catalyst (Scheme 39). In 2019, Kappe and colleagues [36] reported a method to complete perfluoroalkylation of olefins under visible light in flow. Perfluoroalkylated olefin 118 was prepared by employing olefin 116 and perfluoroalkyl iodides 117 as substrates as well as

• triethylamine as additive at 20 °C and under 405 nm irradiation (Scheme 40). A standard residence time of 5 min was required for the full conversion via the EDA complex that formed by alkene and perfluoroalkyl iodide in flow, while longer residence times were requisite for less reactive alkenes. Moreover, the

• yield of this reaction can reach 7.6 g ⋅ h−1 on a gram scale, indicating that the flow step is promising in photochemistry. In 2019, Aggarwal and colleagues [38] employed Katritzky salt 119 as electron acceptor and HE 79 as electron donor to form an EDA complex, providing the corresponding alkyl radical

[2 + 1] Cycloaddition reactions of fullerene C₆₀ based on diazo compounds

• Yuliya N. Biglova

Beilstein J. Org. Chem. 2021, 17, 630–670, doi:10.3762/bjoc.17.55

• cholesterol 44 and histamine 45. Scientific literature [97] reports a three-step continuous synthesis of [6,6]-tert-butyl phenyl-C61-butyrate 47 based on tert-butyl 4-benzoylbutyrate hydrazone in a microstructured flow reactor that eliminates the need for stage-by-stage isolation of intermediate products and

Synthesis and physicochemical evaluation of fluorinated lipopeptide precursors of ligands for microbubble targeting

• Masayori Hagimori,
• Estefanía E. Mendoza-Ortega and
• Marie Pierre Krafft

Beilstein J. Org. Chem. 2021, 17, 511–518, doi:10.3762/bjoc.17.45

• acetonitrile 20:80 (v/v) at a flow rate of 0.5 mL/min. (SG)5-KSS-K(C2H4-C6F13)2 (1) was synthesized according to the general procedure using 4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononanoic acid. Yield: 121 mg (6.3%); FABMS (m/z): 1916 [M + H]+; HRMS (m/z): [M + H]+ calcd for C61H84F26N17O23, 1916.5511; found

Biochemistry of fluoroprolines: the prospect of making fluorine a bioelement

• Vladimir Kubyshkin,
• Rebecca Davis and
• Nediljko Budisa

Beilstein J. Org. Chem. 2021, 17, 439–460, doi:10.3762/bjoc.17.40

Synthesis of trifluoromethyl ketones by nucleophilic trifluoromethylation of esters under a fluoroform/KHMDS/triglyme system

• Yamato Fujihira,
• Yumeng Liang,
• Makoto Ono,
• Kazuki Hirano,
• Takumi Kagawa and
• Norio Shibata

Beilstein J. Org. Chem. 2021, 17, 431–438, doi:10.3762/bjoc.17.39

• equivalents of KHMDS. Further application of this “batch protocol” for a “continuous-flow microreactor” reaction is now ongoing in our laboratory towards industrial collaboration. Experimental A test tube containing 1 (0.4 mmol) in triglyme (0.7 mL) was charged with HCF3 (9.9 mL, 1.1 equiv, measured by a