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

Grip on complexity in chemical reaction networks

• Albert S. Y. Wong and
• Wilhelm T. S. Huck

Beilstein J. Org. Chem. 2017, 13, 1486–1497, doi:10.3762/bjoc.13.147

• network motif based on autocatalytic production and delayed inhibition of an enzyme that was kept out-of-equilibrium. (d) Schematic representation of the flow reactor that is used to implement flow. (e) The output of the reactor was measured using an enzymatic activity in an offline analysis. The response

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97

• micromixer followed by a flow reactor (usually depicted in the form of a helical coil or a packed column), which is maintained at a desired temperature or a given temperature profile. The outlet stream of the reactor is subsequently mixed with the new reagent and allowed to react for further transformation

• temperature profiles inside the reactor. Whenever it is not possible to insert temperature sensors along the flow reactor/microreactor due to its compact dimensions (although miniaturized sensors are available almost everywhere), the temperature should be monitored at the inlet (preferably at mixing points

• and also to avoid undesired side reactions possibly due to prolonged contact of the reactants. The mixed stream has to be followed by a flow reactor with a jacket, where the jacket side fluid can be the manipulating variable whereas the outlet concentration of the reactor can be set as a control

Continuous-flow processes for the catalytic partial hydrogenation reaction of alkynes

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

Beilstein J. Org. Chem. 2017, 13, 734–754, doi:10.3762/bjoc.13.73

• the hydrogenation of 3, the ex-situ particles were deposited onto a ZnO/Sintered Metal Fibers support, having selected this material for its excellent mass transfer properties. The catalyst was then integrated into a bubble column flow reactor with staged catalytic layers, showing two order magnitude

• from a diffusion-controlled to kinetic-limited regime [163][181]. The non-accumulation of co-products adsorbed on the catalyst surface may also significantly contribute to the minimization of active site inhibition under the conditions of continuous flow [27]. Flow reactor design. Performance

• differences among different continuous-flow reactor designs are difficult to rationalize due to the number of additional variables related to the catalyst involved, which include: - the role played by the supported metal, e.g., type, loading, MNP size, shape and location [182][183]), - the role played by the

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

• Flavio Fanelli,
• Giovanna Parisi,
• Leonardo Degennaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2017, 13, 520–542, doi:10.3762/bjoc.13.51

• Ar–Csp3, Ar–Csp2 and Ar–Csp bond-forming reactions. The use of a photochemical flow reactor, consisting of a polyfluorinated tube reactor wrapped around a 500 W Hg lamp, allowed to overcome batch limitations paving the way for metal-free arylation reactions via phenyl cations. Derivatives 14a–g were

• artemisinic acid. Flow reactor system for multistep synthesis of (S)-rolipram. Pumps are labelled a, b, c, d and e; Labels A, B, C, D, E and F are flow lines. X are molecular sieves; Y is Amberlyst 15Dry; Z is Celite. (Reproduced with permission from [84], copyright 2015 Nature Publishing Group).

NMR reaction monitoring in flow synthesis

• M. Victoria Gomez and
• Antonio de la Hoz

Beilstein J. Org. Chem. 2017, 13, 285–300, doi:10.3762/bjoc.13.31

• planning, interpreting results and developing new projects. In this regard, flow chemistry is the central motif of this automated approach. In contrast to batch mode, in flow chemistry the starting materials are continuously introduced into the flow reactor (e.g., a microreactor or a column) and the

• product is continuously eluted from the end of the flow reactor. This approach can be used from microscale to laboratory scale and even to production scale [4][5]. Some important advantages of flow chemistry are: Diffusion is clearly improved with regard to chemistry in batch (reagents and products), thus

• second flow reactor the Grignard was reacted with CO2 to obtain carboxylic acids (Figure 5). The whole process was monitored by on-line 1H NMR spectroscopy using a low field NMR instrument (Spinsolve-60 from Magritek). The reaction was analysed by in-line NMR and off-line with a standard NMR tube. In the

Diels–Alder reactions of myrcene using intensified continuous-flow reactors

• Christian H. Hornung,
• Miguel Á. Álvarez-Diéguez,
• Thomas M. Kohl and
• John Tsanaktsidis

Beilstein J. Org. Chem. 2017, 13, 120–126, doi:10.3762/bjoc.13.15

• different naturally occurring and synthetic dienophiles. The synthesis of the Diels–Alder adduct from myrcene and acrylic acid, containing surfactant properties, was scaled-up in a plate-type continuous-flow reactor with a volume of 105 mL to a throughput of 2.79 kg of the final product per day. This

• continuous flow [22][23]. Over the past years, Diels–Alder reactions of isoprene using laboratory-scale flow reactors were studied by different research groups [24][25]. A continuous-flow reactor can offer a range of benefits over batch processing, with the enhanced heat and mass transfer arguable being one

• R2/R4 tubular flow reactor to a reaction volume of typically 20 mL and then on a Chemtrix Plantrix® MR260 plate flow reactor to a reaction volume of typically 200 mL (see also experimental section). The results from these continuous-flow experiments are shown in Table 3. The 10-times scale-up in the

3D printed fluidics with embedded analytic functionality for automated reaction optimisation

• Andrew J. Capel,
• Andrew Wright,
• Matthew J. Harding,
• George W. Weaver,
• Yuqi Li,
• Russell A. Harris,
• Steve Edmondson,
• Ruth D. Goodridge and
• Steven D. R. Christie

Beilstein J. Org. Chem. 2017, 13, 111–119, doi:10.3762/bjoc.13.14

• flow reactor. Notable recent work in this area has been carried out by Cronin [14], Ley [15] and Jensen [16]. This research highlights the array of benefits that manufacturing fluidic devices via AM processes can bring, including the ability to produce multimaterial parts with complex microscale

Continuous-flow synthesis of primary amines: Metal-free reduction of aliphatic and aromatic nitro derivatives with trichlorosilane

• Riccardo Porta,
• Alessandra Puglisi,
• Giacomo Colombo,
• Sergio Rossi and
• Maurizio Benaglia

Beilstein J. Org. Chem. 2016, 12, 2614–2619, doi:10.3762/bjoc.12.257

• the reaction (the first few hours). Having demonstrated that the flow transformation is very fast we next explored reaction scale-up employing a bigger flow reactor (5 mL PTFE reactor, i.d. = 2.54 mm, l = 100 cm), in order to increase the productivity of the process. Using the same reaction set-up

• full conversion of the starting material no further purification was required. Continuous flow reduction of 4-nitrobenzophenone using a 0.5 mL PTFE flow reactor. Continuous flow reduction of aromatic nitro compounds. Continuous-flow reduction of aliphatic nitro compounds. Synthesis of 2-(4’-chlrophenyl

• )aniline (4) with a 5 mL flow reactor. Synthesis of intermediate 6, a direct precursor of the drug baclofen. Continuous-flow reduction of 1a and in-line extraction. Screening of reaction conditions. Scope of the reaction (see Scheme 2). Supporting Information Supporting Information File 488: General

Development of a continuous process for α-thio-β-chloroacrylamide synthesis with enhanced control of a cascade transformation

• Olga C. Dennehy,
• Valérie M. Y. Cacheux,
• Benjamin J. Deadman,
• Denis Lynch,
• Stuart G. Collins,
• Humphrey A. Moynihan and
• Anita R. Maguire

Beilstein J. Org. Chem. 2016, 12, 2511–2522, doi:10.3762/bjoc.12.246

• , due to the neutralisation of HCl – a byproduct – with triethylamine, and the need for effective heat removal imposes limitations on the batch scale-up of this step. It was envisaged that the efficient heat transfer properties of a high surface area tubular flow reactor would remove the need for

• . Indeed, trial runs of a continuous process in ethyl acetate resulted in immediate blockage of the flow reactor at the point of reagent mixing. To prevent blockages due to salt formation we investigated replacements for triethylamine that would produce a more soluble HCl salt. Diisopropylethylamine (DIPEA

The in situ generation and reactive quench of diazonium compounds in the synthesis of azo compounds in microreactors

• Faith M. Akwi and
• Paul Watts

Beilstein J. Org. Chem. 2016, 12, 1987–2004, doi:10.3762/bjoc.12.186

• and acidic azo coupling conditions. Comparison of reaction conversion attained from two continuous flow reactor systems. Experimental domain. Experimental domain. Supporting Information Supporting Information File 442: Additional diagrams and NMR spectra. Acknowledgements We would like to thank the