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

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

• mixing elements, reactor residence coils, heating/cooling segments and additional downstream components such as phase separators, quenching stages and crystallisers. A typical flow reactor will comprise two or more pumps (isocratic/peristaltic/syringe) that feed an HPLC manifold (into which samples may

• flow [86]. Due to the inherently low active volumes of reactants that are processed in the reaction zone within a continuous-flow reactor, the safety risks associated with critical event are greatly diminished. In addition, process reliance and sustainability are further improved by adding extra safety

• %) over 10 hours of continuous runtime [155]. As such a simple chromatographic column can be exploited as flow reactor to perform initial feasibility tests. As with all condensation reactions, the main problem when performed in flow is the elimination of water. Yeung et al. provided a solution using a

[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

A sustainable strategy for the straightforward preparation of 2H-azirines and highly functionalized NH-aziridines from vinyl azides using a single solvent flow-batch approach

• Michael Andresini,
• Leonardo Degannaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2021, 17, 203–209, doi:10.3762/bjoc.17.20

• reaction crudes were re-introduced into the flow reactor under the same conditions, azirines 2h–j were obtained quantitatively (2h, 98%; 2i, 97%; 2j, 97%). Pursuing in our aim to develop a green approach to prepare substituted NH-aziridines from vinyl azides in a single procedure, the solution of 2a from

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

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

• through small-diameter (μm–mm) channels. Lectka and co-workers reported the processing of their benzil-photosensitized enone-directed C(sp3)–H fluorination in a custom-built flow reactor, comprised of a syringe pump, a coil of fluorinated ethylene propylene (FEP) tubing (7.5 m; inner diameter 1.6 mm

Heterogeneous photocatalysis in flow chemical reactors

• Christopher G. Thomson,
• Ai-Lan Lee and
• Filipe Vilela

Beilstein J. Org. Chem. 2020, 16, 1495–1549, doi:10.3762/bjoc.16.125

• the molar attenuation coefficient of the photocatalyst (ε), its concentration (c), and the optical path length (l). This also applies to immobilising an HPCat in a flow reactor, which generally confines and concentrates the material within a transparent vessel with high surface-to-volume ratio

• conjugated polymer and applied the material for singlet oxygen photosensitisation [131]. Both of these were applied as HPCats in a commercial flow reactor for photocatalysis. Whilst flow chemistry is generally used to enhance the efficiency of HPC processes, we recently demonstrated that it can also enhance

Disposable cartridge concept for the on-demand synthesis of turbo Grignards, Knochel–Hauser amides, and magnesium alkoxides

• Mateo Berton,
• Kevin Sheehan,
• Andrea Adamo and
• D. Tyler McQuade

Beilstein J. Org. Chem. 2020, 16, 1343–1356, doi:10.3762/bjoc.16.115

• fresh organomagnesium reagents on a discovery scale and will do so independent from the operator’s experience in flow and/or organometallic chemistry. Keywords: Knochel–Hauser base; lithium chloride; magnesium; on-demand; packed-bed reactors; plug and flow reactor; synthesizer; turbo Grignard reagent

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

• centered on the combination of light with continuous flow reactors [1][2][3][4][5][6]. The reason for this increased interest is that continuous flow photochemical reactors can overcome various limitations that occur when the same reaction run in batch reactors [7]. For example, the flow reactor can

• , which, for a flow reactor, is the product of the light intensity and time [27][28][29]. The light intensity can be considered as the limiting factor in a flow setup as the space around the reaction channel is limited, as is the power of the light source. The exposure time has less limitations as it is

• reagent uses the Bouguer–Lambert–Beer law as a starting point to estimate a concentration close to the optimum. The law in its basic definition is not entirely applicable to a flow reactor but will nevertheless provide a convenient starting point [30][31]. The analysis of the required concentration of the

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

• and propylene oxide as a proton scavenger under flow conditions (0.05 mL/min; residence time = 20 h). The use of flow conditions drastically enhanced the kinetics of the reaction, moving from 120 h reaction time in batch to 20 h using a continuous flow reactor. The reaction allowed the synthesis of a

Visible-light-induced addition of carboxymethanide to styrene from monochloroacetic acid

• Kaj M. van Vliet,
• Nicole S. van Leeuwen,
• Albert M. Brouwer and
• Bas de Bruin

Beilstein J. Org. Chem. 2020, 16, 398–408, doi:10.3762/bjoc.16.38

• shell. We anticipated that in a flow setup using tubing with a small internal diameter (0.71 mm) the photocatalyzed reaction pathways could be more efficient. However, in this case, performing the reaction under flow conditions did not lead to better results. The reaction performed in a flow reactor led

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

• reaction was quenched within the flow reactor using aqueous HCl (0.11 M, 1.1 equiv) when necessary. Samples were collected and analysed using HPLC resulting in 4.84 min retention time for azide 5. For characterisation, an appropriate amount of toluene and water was added to the reaction mixture after

Tuning the stability of alkoxyisopropyl protection groups

• Zehong Liang,
• Henna Koivikko,
• Mikko Oivanen and
• Petri Heinonen

Beilstein J. Org. Chem. 2019, 15, 746–751, doi:10.3762/bjoc.15.70

• ., 8a (Figure 2). Recently, the same kind of enol ether formation was considered in connection to an optimization of the conditions for MIP protection on secondary and benzylic hydroxy groups of mandelonitrile derivatives in a flow reactor process [9]. All of the studied acetals are stable toward basic

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

• in flow chemistry. We developed a rack of four syringe pumps controlled by one Arduino computer, which can be manufactured with a commonly available 3D printer and readily available parts. Also, we printed various flow reactor cells, which are fully customizable for each individual reaction. With

• systems is the low chemical resistance of the used printing materials towards most organic solvents [11]. For the development and construction of our flow reactor we had to print and design numerous devices in order to find the most suitable parameters. All reactors were printed with a filament flow of

• performed under batch conditions according to the literature [38] (Scheme 3). The following conversion of glucose 4 into trichloroacetimidate 5 was done in a flow reactor type R1 with a reaction time of 3.5 min. This way, a yield of 67% was obtained for this glycosylation step. Once again we found that

Assessing the possibilities of designing a unified multistep continuous flow synthesis platform

• Mrityunjay K. Sharma,
• Roopashri B. Acharya,
• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2018, 14, 1917–1936, doi:10.3762/bjoc.14.166

• a flow reactor tube of required length and diameter or a microchannel reactor having various geometries or a static mixer) or a continuous stirred tank reactor or a fixed bed reactor or other intensified process equipment viz. spinning disc reactor, impinging jet reactor etc.) and a thermostat which

• , multiple temperature zones can also be provided if required. The reactor module also includes mixers (M1–M9) that are commonly used in flow chemistry [64][65]. The continuous flow reactor can also be equipped with in-line static mixing elements [63]. The second module includes the intermediate storage

Mild and selective reduction of aldehydes utilising sodium dithionite under flow conditions

• Nicole C. Neyt and
• Darren L. Riley

Beilstein J. Org. Chem. 2018, 14, 1529–1536, doi:10.3762/bjoc.14.129

• %, respectively. Flow-based reduction of aldehydes and ketones In developing a flow protocol a Uniqsis FlowSyn Stainless Steel Flow reactor with a Multi X automated sampler was utilized. The reactor set-up (Figure 1) involved the use of two HPLC pumps, a 2 mL mixing chip connected in series to a 14 mL HT PTFE

• process can be run continuously with minimal loss in reactor productivity. Uniqsis FlowSyn Stainless Steel Flow reactor. Flow reactor configuration for the reduction of aldehydes and ketones. NMR spectra showing the optimisation of the dithionite reduction for the reduction of benzaldehyde. Selective

• reduction of an aldehyde in the presence of a ketone. Flow reactor set-up for the continuous reduction of aldehydes. Sodium dithionite-mediated reductions under basic conditions. Reduction of aldehydes and ketones under batch and flow conditions. Optimization of the reduction of benzaldehyde under flow

Cobalt–metalloid alloys for electrochemical oxidation of 5-hydroxymethylfurfural as an alternative anode reaction in lieu of oxygen evolution during water splitting

• Jonas Weidner,
• Stefan Barwe,
• Kirill Sliozberg,
• Stefan Piontek,
• Justus Masa,
• Ulf-Peter Apfel and
• Wolfgang Schuhmann

Beilstein J. Org. Chem. 2018, 14, 1436–1445, doi:10.3762/bjoc.14.121

• of the various cobalt–metalloid alloys supported on Ni RDE electrodes revealed CoB to be the most efficient HMF oxidation catalyst. Using a CoB modified Ni foam as anode material, and Ni foam as the cathode in a continuous flow reactor with an anion exchange membrane separating the anodic and

• of the activities of all investigated CoX-based catalysts (X = B, Si, P, As and Te) is highlighted in Table 1. HMF oxidation in a continuous flow reactor The surprisingly high HMF oxidation activity of CoB made it especially interesting to further study the product distribution and FDCA yield in a

• continuous mode. For this, a flow reactor was employed which contains two nickel foam (NF) electrodes separated by an anion exchange membrane (Supporting Information File 1, Figure S2). The NF anode (1 cm × 1 cm) was modified with CoB by means of spray coating while pure NF was used as cathode material. The

[3 + 2]-Cycloaddition reaction of sydnones with alkynes

• Veronika Hladíková,
• Jiří Váňa and
• Jiří Hanusek

Beilstein J. Org. Chem. 2018, 14, 1317–1348, doi:10.3762/bjoc.14.113

• solid-supported CuSAC reaction in batch or flow reactor.

Biocatalytic synthesis of the Green Note trans-2-hexenal in a continuous-flow microreactor

• Morten M. C. H. van Schie,
• Tiago Pedroso de Almeida,
• Gabriele Laudadio,
• Florian Tieves,
• Elena Fernández-Fueyo,
• Timothy Noël,
• Isabel W. C. E. Arends and
• Frank Hollmann

Beilstein J. Org. Chem. 2018, 14, 697–703, doi:10.3762/bjoc.14.58

• overcome by conducting the reaction in a flow-reactor setup reaching unpreceded catalytic activities for the enzyme in terms of turnover frequency (up to 38 s−1) and turnover numbers (more than 300000) pointing towards preparative usefulness of the proposed reaction scheme. Keywords: alcohol oxidase

• reactor enzymatic oxidation Next, we performed the PeAAOx-catalysed oxidation of trans-hex-2-enol in a slug-flow reactor setup (Supporting Information File 1, Figure S1 and Figures S9–S11). In a first set of experiments we systematically varied the residence time of the reaction mixture in the flow

• decreasing the flow rates and using a longer flow reactor (6 mL volume instead of 3 mL). Pleasingly, already in these first experiments a TN for the enzyme of more than 300000 was observed at long residence times. This also underlines the robustness of the enzyme under the flow conditions. Compared to Figure

High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine

• Eric Yu,
• Hari P. R. Mangunuru,
• Nakul S. Telang,
• Caleb J. Kong,
• Jenson Verghese,
• Stanley E. Gilliland III,
• Saeed Ahmad,
• Raymond N. Dominey and
• B. Frank Gupton

Beilstein J. Org. Chem. 2018, 14, 583–592, doi:10.3762/bjoc.14.45

• resonance of residual CHCl3 (or 0 ppm of TMS) for proton spectra and the 77.23 ppm resonance of CDCl3 for carbon spectra were used as internal references. Continuous-flow experiments were carried out using the E-series flow reactor instrument purchased from Vapourtec Ltd. PFA tubing (1/16 OD × 1 mm ID) was

• ); 13C NMR (125 MHz, CDCl3) δ 207.4, 44.0, 30.3, 27.2, 6.7. Spectra were obtained in accordance with those previously reported [3]. Synthesis of 5-(ethyl(2-hydroxyethyl)amino)pentan-2-one (6) Telescope of compound 6: Prior to the start of the experiment, the flow reactor unit was rinsed with dry THF and

• previously reported [38][39]. Synthesis of (E)-5-(ethyl(2-hydroxyethyl)amino)pentan-2-one oxime (11) Flow: Prior to the start of the experiment, the flow reactor unit was rinsed with dry THF and flushed with nitrogen gas. At room temperature, the stock solutions of 5-iodopentan-2-one (10, 1.0 M) and 2

Continuous multistep synthesis of 2-(azidomethyl)oxazoles

• Thaís A. Rossa,
• Nícolas S. Suveges,
• Marcus M. Sá,
• David Cantillo and
• C. Oliver Kappe

Beilstein J. Org. Chem. 2018, 14, 506–514, doi:10.3762/bjoc.14.36

• reactors for each step were setup, the reaction conditions re-optimized when necessary, and finally all the steps integrated in a single continuous stream. The thermolysis of vinyl azide 1 was performed in a continuous flow reactor consisting of a perfluoroalkoxy (PFA) coil (0.5 mL, 0.8 mm i.d.) immersed

• phase. Decomposition of 2-(bromomethyl)oxazoles 6 was successfully avoided by further integrating into the continuous-flow reactor the final nucleophilic halide displacement step with NaN3. The resulting 2-(azidomethyl)oxazole derivatives 7 presented higher stability and could be isolated without

• to give the desired product. After optimization of all individual steps in batch and continuous-flow mode, the complete sequence has been integrated in a single continuous-flow reactor, in which the vinyl azide is fed as substrate and the final 2-(azidomethyl)oxazole is formed and collected from the

Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review

• Fabio Tonin and
• Isabel W. C. E. Arends

Beilstein J. Org. Chem. 2018, 14, 470–483, doi:10.3762/bjoc.14.33

• production of UDCA. Different chemical, chemoenzymatic and enzymatic routes will be considered. In addition, the precursors availability as well as the substrate loading in the process and the requisites for potential new routes will be discussed. Furthermore, the potential benefits of a flow reactor setup

• dehydroxylation reactions are highlighted with a red, blue and green arrow, respectively. Names of compounds are indicated in the box. The general stereoinformation of steroid scaffold is shown in Figure 2. R = 4-pentanoic acid. Schematic representation of the flow reactor for the continuous conversion of CDCA to

Continuous-flow retro-Diels–Alder reaction: an efficient method for the preparation of pyrimidinone derivatives

• Imane Nekkaa,
• Márta Palkó,
• István M. Mándity and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2018, 14, 318–324, doi:10.3762/bjoc.14.20

• were selected on the basis of the solubility of the starting materials. A schematic representation of the flow reactor setup is illustrated in Figure 1. Products 9–14 thus prepared were identified by means of HPLC–MS and NMR spectroscopic analysis. All physical and spectroscopic data of pyrimidinones 9

• our system. Surprisingly, however, we could detect traces of di-endo-3-phenyl-4a,5,8,8a-tetrahydro-5,8-ethanoquinazolin-4(3H)-one (15b), resulting from desulfurisation of 8b (Scheme 2). This observation prompted us to investigate whether desulfurisation can occur under the flow reactor conditions. In

• requiring harsh conditions in batch methods. A simple, efficient and scalable production was implemented with a short processing time, which might open up new horizons for a potential CF industrial synthesis of heterocycles. Schematic outline of the continuous-flow reactor. Flow synthesis for the

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

• trifluoromethylation with CF3SO2Na are highly efficient, the original Langlois’ conditions were nevertheless applied to a series of heteroarenes. Li and co-workers reported the synthesis of 3-trifluoromethylcoumarins 64 by Cu(I)-catalysed trifluoromethylation with CF3SO2Na and t-BuOOH in a continuous-flow reactor [61

• ]. After optimisation of the reaction conditions in batch, the optimal reaction conditions were established in a continuous-flow reactor at a flow rate of 100 µL min−1 at 60 °C for 40 min. The substrate scope was evaluated on 11 coumarins and showed that both electron-rich and electron-deficient functional

A concise flow synthesis of indole-3-carboxylic ester and its derivatisation to an auxin mimic

• Marcus Baumann,
• Ian R. Baxendale and
• Fabien Deplante

Beilstein J. Org. Chem. 2017, 13, 2549–2560, doi:10.3762/bjoc.13.251

• ). EtOAc was promising and made extraction very easy but during the reactions small quantities of a dark red, sticky, precipitate were observed (Table 1, entry 12). This was considered problematic for processing in a meso flow reactor due to the potential for causing blockages. It was however found that

• cyclisation products 12 and 14, assigned structure of byproduct 15. Synthetic strategy towards desired indole product 8. Initial flow reactor setup for the synthesis of intermediate 11. Coflore ACR setup for the synthesis of intermediate 11. Quenching and work-up of the reaction stream from the Coflore ACR