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

• 1,2-dichloroethane and air could react efficiently inside a pressurized microfluidic channel at high temperature in the flow microreactor. It is important to be noted that precise control of reaction temperature and residence time in our flow system are keys to inhibit overreactions in cyclohexene

• with air in the flow microreactor A flow microreactor system consisting of a T-shaped micromixer, and one microtube reactor was used for epoxidation of cyclohexene with air. A solution of cyclohexene (0.065 M), isobutyraldehyde (0.195 M), and tridecane as an internal standard in 1,2-dichloroethane

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

• time, extremely fast molecular diffusion, and expelling the reaction product to avoid over-oxidation or over-reduction. We have previously reported the electrochemical carboxylation of several imines in a flow microreactor to afford the corresponding α-amino acids in good to moderate yields [33][34][35

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

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

When metal-catalyzed C–H functionalization meets visible-light photocatalysis

• Lucas Guillemard and
• Joanna Wencel-Delord

Beilstein J. Org. Chem. 2020, 16, 1754–1804, doi:10.3762/bjoc.16.147

• applied to various C–H functionalization reactions [92][93]. In 2017, Noël, Van der Eycken and co-workers hence astutely combined the dual catalysis strategy with flow microreactor technology to achieve C2-acylation of indole derivatives with aldehydes (Figure 30) [94]. Both electron-rich and electron

Photocatalytic trifluoromethoxylation of arenes and heteroarenes in continuous-flow

• Alexander V. Nyuchev,
• Ting Wan,
• Borja Cendón,
• Carlo Sambiagio,
• Job J. C. Struijs,
• Michelle Ho,
• Moisés Gulías,
• Ying Wang and
• Timothy Noël

Beilstein J. Org. Chem. 2020, 16, 1305–1312, doi:10.3762/bjoc.16.111

• , Road, North Chicago, Illinois 60064, United States of America 10.3762/bjoc.16.111 Abstract The first example of photocatalytic trifluoromethoxylation of arenes and heteroarenes under continuous-flow conditions is described. Application of continuous-flow microreactor technology allowed to reduce the

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

• described in the literature to alleviate the inactivation issue described above [9][10][11][12]. The continuous-flow microreactor technology has emerged as a safe and scalable way to approach oxidation reactions [13][14]. Due to its small dimensions, hazardous reactions can be easily controlled, owing to

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

• following characteristics: a) fast mixing: in a flow microreactor, in striking contrast to batch conditions, mixing takes place by molecular diffusion so that a concentration gradient can be avoided; b) high surface-to-volume ratio: the microstructure of microreactors allows for a very rapid heat transfer

• both organic and sustainable synthesis involving chemical transformations that are very difficult or practically impossible to conduct using conventional batch conditions. With the aim to show how flow microreactor technology and flash chemistry could contribute to the development of a sustainable

• at −78 °C. Under these flow conditions, the aldehyde or ketone carbonyl moiety can survive the nucleophilic organolithium attack. Remarkably, the flow microreactor system allowed also the generation of benzyllithiums at 20 °C, rather than under cryogenic (−95 °C) conditions adopted with a

Continuous-flow synthesis of highly functionalized imidazo-oxadiazoles facilitated by microfluidic extraction

• Ananda Herath and
• Nicholas D. P. Cosford

Beilstein J. Org. Chem. 2017, 13, 239–246, doi:10.3762/bjoc.13.26

• from the Mass Spectrometry Core at the Sanford Burnham Prebys Medical Discovery Institute (Orlando, Florida). LC–MS analyses were carried out on a Shimadzu LC–MS 2010 Series LC System with a Kromasil 100 5 micron C18 column (50 × 2.1 mm i.d.). Continuous-flow (microreactor) experiments were carried out

Carbon–carbon bond cleavage for Cu-mediated aromatic trifluoromethylations and pentafluoroethylations

• Tsuyuka Sugiishi,
• Hideki Amii,
• Kohsuke Aikawa and
• Koichi Mikami

Beilstein J. Org. Chem. 2015, 11, 2661–2670, doi:10.3762/bjoc.11.286

• reaction temperature from 160 °C to 200 °C accelerated the decarboxylation of CF3CO2K [36] (Scheme 3). The trifluoromethylation using a microreactor resulted in a good yield within a short reaction time by virtue of the thermal stability of CF3Cu and control of mixing. Taking advantage of the flow

• microreactor, a new protocol for scalable aromatic trifluoromethylation was developed. From a mechanistic aspect, Vicic and co-workers explored the direct generation of CF3Cu from CF3CO2Cu. The use of (N-heterocyclic carbene)copper-trifluoroacetates prepared from trifluoroacetic acid (TFA) was investigated in

Synthesis and immunological evaluation of protein conjugates of Neisseria meningitidis X capsular polysaccharide fragments

• Laura Morelli,
• Damiano Cancogni,
• Marta Tontini,
• Alberto Nilo,
• Sara Filippini,
• Paolo Costantino,
• Maria Rosaria Romano,
• Francesco Berti,
• Roberto Adamo and
• Luigi Lay

Beilstein J. Org. Chem. 2014, 10, 2367–2376, doi:10.3762/bjoc.10.247

• fragments, based on the synthetic improvements and also the benefits of the continuous-flow microreactor technology herein described, is currently ongoing in our laboratory and it will be reported in due course. Besides the length of the carbohydrate haptens, the saccharide loading onto the protein is

Continuous flow nitration in miniaturized devices

• Amol A. Kulkarni

Beilstein J. Org. Chem. 2014, 10, 405–424, doi:10.3762/bjoc.10.38

• continuous flow microreactor

Flow microreactor synthesis in organo-fluorine chemistry

• Hideki Amii,
• Aiichiro Nagaki and
• Jun-ichi Yoshida

Beilstein J. Org. Chem. 2013, 9, 2793–2802, doi:10.3762/bjoc.9.314

• faced with problems such as the difficulties in handling of fluorinating reagents and in controlling of chemical reactions. Recently, flow microreactor synthesis has emerged as a new methodology for producing chemical substances with high efficiency. This review outlines the successful examples of

• synthesis and reactions of fluorine-containing molecules by the use of flow microreactor systems to overcome long-standing problems in fluorine chemistry. Keywords: defluorination; fluorine; fluorination; flow microreactor; organo-fluorine; perfluoroalkylation; Review Fluorine is a key element in the

• fluorine chemistry. Meanwhile, flow microreactor synthesis, the use of microfluidic devices, has emerged as a new method for producing chemical substances with high efficiency [11][12][13]. Now, the introduction of continuous-flow synthesis technique to laboratory synthesis represents a highly useful and

A combined continuous microflow photochemistry and asymmetric organocatalysis approach for the enantioselective synthesis of tetrahydroquinolines

• Erli Sugiono and
• Magnus Rueping

Beilstein J. Org. Chem. 2013, 9, 2457–2462, doi:10.3762/bjoc.9.284

• ] could provide the desired enantioenriched tetrahydroquinolines (Scheme 1) [38]. Results and Discussion The continuous-flow microreactor system for the experiment was set up according to Scheme 2. The flow device was set up with multiple commercially available glass reactors connected in parallel and

• and subsequent asymmetric reduction to afford the corresponding tetrahydroquinolines in good yields and high enantioselectivities. Conclusion In conclusion, we have demonstrated the great potential of a new continuous-flow microreactor system for the photocyclization–reduction cascade of 2

Ethyl diazoacetate synthesis in flow

• Mariëlle M. E. Delville,
• Jan C. M. van Hest and
• Floris P. J. T. Rutjes

Beilstein J. Org. Chem. 2013, 9, 1813–1818, doi:10.3762/bjoc.9.211

• chemical synthesis is performed. In particular continuous-flow microreactor technology offers multiple advantages over batch chemistry, including the inherently safe conducting of reactions due to the small reactor dimensions, efficient heat transport and excellent control over the reaction conditions [6

Flow Giese reaction using cyanoborohydride as a radical mediator

• Takahide Fukuyama,
• Takuji Kawamoto,
• Mikako Kobayashi and
• Ilhyong Ryu

Beilstein J. Org. Chem. 2013, 9, 1791–1796, doi:10.3762/bjoc.9.208

• precursors, ethyl acrylate as a radical trap, and sodium cyanoborohydride as a radical mediator, were examined in a continuous flow system. With the use of an automated flow microreactor, flow reaction conditions for the Giese reaction were quickly optimized, and it was found that a reaction temperature of

• , equipped with a static mixer having 150 μm width and an automated fraction collector. Using the optimized flow conditions (70 °C, 10–15 min), high yielding conversions of 1b to 3b and 1c to 3c were also obtained. Pictures of the flow microreactor system (MiChS® System X-1), a micromixer (MiChS β-150

Gallium-containing polymer brush film as efficient supported Lewis acid catalyst in a glass microreactor

• Rajesh Munirathinam,
• Roberto Ricciardi,
• Richard J. M. Egberink,
• Jurriaan Huskens,
• Michael Holtkamp,
• Herbert Wormeester,
• Uwe Karst and
• Willem Verboom

Beilstein J. Org. Chem. 2013, 9, 1698–1704, doi:10.3762/bjoc.9.194

• ; polymer brushes; Introduction Heterogeneous catalysis plays a crucial role in organic synthesis both in industry and academia. In the present situation, microreactors offer a number of benefits over classical setups [1][2][3]. Especially, heterogeneous catalysis in a continuous-flow microreactor is

• = 9.251 keV) was quantified by using strontium (Kα1 = 9.251 keV) as internal standard ([Sr] = 10.0 µg/mL). Quantification was performed by the Bruker Spectra software (version 6.1.5.0) and based on the known concentration of the internal standard. Set up of the flow microreactor All microreactor

Inter- and intramolecular enantioselective carbolithiation reactions

• Asier Gómez-SanJuan,
• Nuria Sotomayor and
• Esther Lete

Beilstein J. Org. Chem. 2013, 9, 313–322, doi:10.3762/bjoc.9.36

• concept to avoid the epimerization of reactive intermediates, which has allowed them to carry out the enantioselective version of the above procedure. Thus, the use of a flow microreactor system has allowed the enantioselective carbolithiation of conjugated enynes, followed by the reaction with

Continuous-flow catalytic asymmetric hydrogenations: Reaction optimization using FTIR inline analysis

• Magnus Rueping,
• Teerawut Bootwicha and
• Erli Sugiono

Beilstein J. Org. Chem. 2012, 8, 300–307, doi:10.3762/bjoc.8.32

• example of a continuous-flow organocatalytic asymmetric transfer hydrogenation performed in a microreactor. In this work a ReactIR flow cell was coupled with the microreactor and applied as an inline monitoring device for optimizing the reactions. Results and Discussion The continuous-flow microreactor

Multistep flow synthesis of vinyl azides and their use in the copper-catalyzed Huisgen-type cycloaddition under inductive-heating conditions

• Lukas Kupracz,
• Jan Hartwig,
• Jens Wegner,
• Sascha Ceylan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2011, 7, 1441–1448, doi:10.3762/bjoc.7.168

• ] or copper-on-charcoal (Cu/C) [30], can serve as a catalytic source that promotes the CuAAC. Bogdan et al. combined this observation with flow technology by using a custom-made heated copper flow reactor [31]. We successfully implemented the CuAAC by inductively heating copper wire inside a flow

• microreactor [32]. A key benefit of this technology is that the copper metal is directly and instantaneously heated inside the reactor, which results in a higher reactivity than with conventionally heated elemental copper [32]. These results prompted us to investigate the reaction of vinyl azides 4 in the

Translation of microwave methodology to continuous flow for the efficient synthesis of diaryl ethers via a base-mediated S_NAr reaction

• Charlotte Wiles and
• Paul Watts

Beilstein J. Org. Chem. 2011, 7, 1360–1371, doi:10.3762/bjoc.7.160

• ® S1) was employed for the continuous flow synthesis of diaryl ethers at 195 °C and 25 bar, affording a reduction in reaction time from tens of minutes to 60 s when compared with a stopped-flow microwave reactor. Keywords: automated synthesis; continuous flow; microreactor; microwave; nucleophilic

Scaling up of continuous-flow, microwave-assisted, organic reactions by varying the size of Pd-functionalized catalytic monoliths

• Ping He,
• Stephen J. Haswell,
• Paul D. I. Fletcher,
• Stephen M. Kelly and
• Andrew Mansfield

Beilstein J. Org. Chem. 2011, 7, 1150–1157, doi:10.3762/bjoc.7.133

• ][5][6][7]. Much of this work has focused on continuous-flow microreactor methodology for laboratory based organic synthesis, and has featured the development of inorganic and organic polymer based functionalized monolithic reactors that can operate at elevated temperatures and under high pressure [8

• -functionalized monoliths in a flow microreactor, is the achievement of an efficient coupling of the microwave energy, which will be a function of both the absorbing species present and of the penetration depth of microwave irradiation into the reaction zone [17]. This is especially important in flow systems

Homocoupling of aryl halides in flow: Space integration of lithiation and FeCl₃ promoted homocoupling

• Aiichiro Nagaki,
• Yuki Uesugi,
• Yutaka Tomida and
• Jun-ichi Yoshida

Beilstein J. Org. Chem. 2011, 7, 1064–1069, doi:10.3762/bjoc.7.122

• homocoupling of aryllithiums, and this enabled its integration with the halogen–lithium exchange reaction of aryl halides in a flow microreactor. This system allows the homocoupling of two aryl halides bearing electrophilic functional groups, such as CN and NO2, in under a minute. Keywords: homocoupling; iron

• aryllithiums, especially of those bearing electrophilic functional groups such as cyano and nitro groups [21], making the subsequent homocoupling difficult or impossible. Recently, we have reported that flow microreactor systems [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41

• been effectively accomplished in an integrated flow microreactor system. Results and Discussion First, we focused on the generation of p-methoxyphenyllithium from p-bromoanisole (Scheme 1). A flow microreactor system, consisting of two T-shaped micromixers (M1 and M2) and two microtube reactors (R1 and

Continuous gas/liquid–liquid/liquid flow synthesis of 4-fluoropyrazole derivatives by selective direct fluorination

• Jessica R. Breen,
• Graham Sandford,
• Dmitrii S. Yufit,
• Judith A. K. Howard,
• Jonathan Fray and
• Bhairavi Patel

Beilstein J. Org. Chem. 2011, 7, 1048–1054, doi:10.3762/bjoc.7.120

• manufacturing, we developed continuous flow microreactor systems that enabled gas/liquid fluorination reactions between fluorine and various substrates to occur in very efficient processes [19][20][21]. Fluoro-carbonyl derivatives can, in principle, be utilised as building blocks for the preparation of more

Unusual behavior in the reactivity of 5-substituted-1H-tetrazoles in a resistively heated microreactor

• Bernhard Gutmann,
• Toma N. Glasnov,
• Tahseen Razzaq,
• Walter Goessler,
• Dominique M. Roberge and
• C. Oliver Kappe

Beilstein J. Org. Chem. 2011, 7, 503–517, doi:10.3762/bjoc.7.59

• Chemistry, Karl-Franzens-University Graz, Universitätsplatz 1, A-8010 Graz, Austria Continuous Flow/Microreactor Technologies, Lonza AG, CH-3930 Visp, Switzerland 10.3762/bjoc.7.59 Abstract The decomposition of 5-benzhydryl-1H-tetrazole in an N-methyl-2-pyrrolidone/acetic acid/water mixture was