Continuous flow photocyclization of stilbenes – scalable synthesis of functionalized phenanthrenes and helicenes

• Quentin Lefebvre,
• Marc Jentsch and
• Magnus Rueping

Beilstein J. Org. Chem. 2013, 9, 1883–1890, doi:10.3762/bjoc.9.221

• Quentin Lefebvre Marc Jentsch Magnus Rueping Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany 10.3762/bjoc.9.221 Abstract A continuous flow oxidative photocyclization of stilbene derivatives has been developed which allows the scalable synthesis of

• backbone functionalized phenanthrenes and helicenes of various sizes in good yields. Keywords: continuous-flow reactor; flow chemistry; helicenes; light-driven cyclization reaction; photocyclization; stilbenes; Introduction Phenanthrenes are versatile intermediates toward polycyclic aromatic hydrocarbons

• visible light in the presence of a sensitizer [22], but, to the best of our knowledge, no reports on broadly applicable light-induced oxidative photocyclizations in flow are known. Herein, we report the first photocyclization of polysubstituted olefins using a continuous flow process and discuss

Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four medicinally-relevant reactions

• Trevor A. Hamlin and
• Nicholas E. Leadbeater

Beilstein J. Org. Chem. 2013, 9, 1843–1852, doi:10.3762/bjoc.9.215

• Trevor A. Hamlin Nicholas E. Leadbeater Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, CT 06269, USA 10.3762/bjoc.9.215 Abstract An apparatus is reported for real-time Raman monitoring of reactions performed using continuous-flow processing. Its capability

• means of a calibration curve, determine product conversion from Raman spectral data as corroborated by data obtained using NMR spectroscopy. Keywords: flow processing; Raman spectroscopy; reaction monitoring; α,β-unsaturated carbonyl; Introduction Continuous-flow processing is used in the chemical

• interfacing a Raman spectrometer with a scientific microwave unit [31]. This has allowed us to monitor reactions from both a qualitative [32][33][34][35] and quantitative [36][37] perspective. A recent report of the use of Raman spectroscopy for monitoring a continuous-flow palladium-catalyzed cross-coupling

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

• ][7][8]. While the synthesis of diazomethane has been extensively explored in batch [9] and in continuous-flow reactors [10][11], EDA is synthesized via different routes in batch [12][13], but relatively little is known about continuous-flow approaches [14]. Considering the importance of EDA in a wide

• variety of reactions e.g. cyclopropanation, X–H insertion, cycloaddition and ylide formation [13][15], and more recently, in the synthesis of valuable compound classes such as β-keto esters [16] and β-hydroxy-α-diazocarbonyl compounds [17], we aimed to develop an inherently safe continuous-flow EDA

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

• 70 °C in combination with a residence time of 10–15 minutes gave good yields of the desired addition products. Keywords: continuous flow system; cyanoborohydride; flow chemistry; iodoalkanes; microreactor; tin-free Giese reaction; Introduction Organo halides are among the most useful precursors to

• automated microflow reactor [32], which revealed that running the continuous flow reactions at 70 °C for 10–15 min gave good yields of Giese addition products with effective suppression of the byproducts. Results and Discussion We employed an automated microflow reactor system, MiChS® System X-1 [33

The application of a monolithic triphenylphosphine reagent for conducting Ramirez gem-dibromoolefination reactions in flow

• Kimberley A. Roper,
• Malcolm B. Berry and
• Steven V. Ley

Beilstein J. Org. Chem. 2013, 9, 1781–1790, doi:10.3762/bjoc.9.207

• continuous-flow chemistry systems. Monoliths are a single continuous piece of uniformly porous material, prepared by precipitation polymerisation of a functionalised monomer [16][17][18][19][20]. The monolith internal structure varies compared to bead-like supports, consisting of a combination of large

[3 + 2]-Cycloadditions of nitrile ylides after photoactivation of vinyl azides under flow conditions

• Stephan Cludius-Brandt,
• Lukas Kupracz and
• Andreas Kirschning

Beilstein J. Org. Chem. 2013, 9, 1745–1750, doi:10.3762/bjoc.9.201

• the first photochemical transformation of vinyl azides to pyrrole derivatives under continuous-flow conditions. Only recently, we reported the two-step preparation of vinyl azides 1 in mircrostructured flow reactors starting from alkenes 6, using the solid-phase bound iodine azide transfer-reagent 7

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

• with gallium on the microchannel interior in the continuous flow-mode. The dehydration of cinnamaldehyde oxime (1, 25 µM in acetonitrile) was used as a model reaction to study the catalytic activity of the gallium-functionalized microreactor, at 90 °C and 5 atm pressure, generated using a back pressure

• regulator in continuous flow. The conversion of the reagent was monitored online by in-line UV–vis detection, measuring the decrease in the extinction of the solution of oxime 1 at 286 nm. The reaction times were varied by changing the flow rates between 1 and 26 µL·min−1. The reaction showed nearly

The rapid generation of isothiocyanates in flow

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 1613–1619, doi:10.3762/bjoc.9.184

• within a pseudo-/continuous flow process [11][12]. From a synthesis perspective the majority of these endeavours have been directed at enhancing specific reaction safety profiles, identifying new reaction sequences or generating improvements to well-known yet cumbersome transformations [13][14][15][16

Efficient continuous-flow synthesis of novel 1,2,3-triazole-substituted β-aminocyclohexanecarboxylic acid derivatives with gram-scale production

• Sándor B. Ötvös,
• Ádám Georgiádes,
• István M. Mándity,
• Lóránd Kiss and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2013, 9, 1508–1516, doi:10.3762/bjoc.9.172

• acid derivatives in a simple and efficient continuous-flow procedure is reported. The 1,3-dipolar cycloaddition reactions were performed with copper powder as a readily accessible Cu(I) source. Initially, high reaction rates were achieved under high-pressure/high-temperature conditions. Subsequently

• safe and straightforward way. The obtained 1,2,3-triazole-substituted β-aminocyclohexanecarboxylates can be regarded as interesting precursors for drugs with possible biological effects. Keywords: β-amino acids; click chemistry; continuous-flow; copper; flow chemistry; triazoles; Introduction In

• frequently used as building blocks for the synthesis of new peptides and foldamers with possible biological effects [28]. Modern continuous-flow (CF) technologies offer many advantages over classical batch-based procedures [29][30][31][32], including efficient mixing quality [33], excellent heat and mass

Controlled synthesis of poly(3-hexylthiophene) in continuous flow

• Helga Seyler,
• Jegadesan Subbiah,
• David J. Jones,
• Andrew B. Holmes and
• Wallace W. H. Wong

Beilstein J. Org. Chem. 2013, 9, 1492–1500, doi:10.3762/bjoc.9.170

• optimization of large area devices is costly and often impossible to achieve. Continuous-flow synthesis enables straight-forward scale-up of materials compared to conventional batch reactions. In this study, poly(3-hexylthiophene), P3HT, was synthesized in a bench-top continuous-flow reactor. Precise control

• : conjugated polymers; continuous-flow synthesis; controlled polymerization; flow chemistry; organic solar cell materials; Introduction Poly(3-hexylthiophene), P3HT, is the most investigated material in bulk heterojunction (BHJ) organic solar cells (OSC) [1]. The reasons for its dominance in the field include

• film quality. This will almost certainly create problems with the performance consistency of large-area roll-to-roll printed devices. To this end, we have started to examine some key reactions in the synthesis of organic electronic materials using continuous-flow processing [11][12][13]. Continuous

Hypervalent iodine/TEMPO-mediated oxidation in flow systems: a fast and efficient protocol for alcohol oxidation

• Nida Ambreen,
• Ravi Kumar and
• Thomas Wirth

Beilstein J. Org. Chem. 2013, 9, 1437–1442, doi:10.3762/bjoc.9.162

• platforms to perform reactions under continuous flow rather than in batch mode has led to improvements regarding safety and sustainability. Microreactor technology can be beneficial over classical approaches in a variety of chemical reactions. Many reactions can benefit from the properties of microreactors

• . Enhanced mass- and heat transfer and short diffusion distances can lead to better yields within shorter reaction times [15]. Herein, we describe the development of continuous-flow systems using hypervalent iodine reagents in the TEMPO-mediated oxidation of alcohols with the advantage of significantly

• synthetic steps, without the need for isolation or purification of the intermediate aldehyde or ketone. Conclusion In conclusion, a highly efficient and selective continuous-flow reaction for the oxidation of different alcohols was developed. Apart from short reaction times, high conversions and excellent

Metal-free aerobic oxidations mediated by N-hydroxyphthalimide. A concise review

• Lucio Melone and
• Carlo Punta

Beilstein J. Org. Chem. 2013, 9, 1296–1310, doi:10.3762/bjoc.9.146

• peroxyl radical generated in situ is the real epoxidizing agent (Scheme 20). This protocol was successfully applied on a larger scale (1 liter Büchi glass vessel) for the synthesis of propylene oxide from the corresponding propene [56], and more recently under continuous-flow conditions, by means of a new

Camera-enabled techniques for organic synthesis

• Steven V. Ley,
• Richard J. Ingham,
• Matthew O’Brien and
• Duncan L. Browne

Beilstein J. Org. Chem. 2013, 9, 1051–1072, doi:10.3762/bjoc.9.118

• early stages of development were heavily influenced by a consideration of the potential for automated visual monitoring, and indeed this visual monitoring technique co-evolved with the gas-flow reactor as we assessed different gases and their potential reactivity in continuous flow processes. The

Aqueous reductive amination using a dendritic metal catalyst in a dialysis bag

• Jorgen S. Willemsen,
• Jan C. M. van Hest and
• Floris P. J. T. Rutjes

Beilstein J. Org. Chem. 2013, 9, 960–965, doi:10.3762/bjoc.9.110

• utilized for purification purposes after the reaction [22] and in continuous-flow reactors during the reaction [23]. Dendritic catalysts have also been applied while enclosed in commercially available dialysis bags [24][25][26]. The latter examples, however, were conducted in organic, environmentally

3D-printed devices for continuous-flow organic chemistry

• Vincenza Dragone,
• Victor Sans,
• Mali H. Rosnes,
• Philip J. Kitson and
• Leroy Cronin

Beilstein J. Org. Chem. 2013, 9, 951–959, doi:10.3762/bjoc.9.109

• synthesis; millifluidics; reactionware; Introduction The use of flow chemistry and 3D-printing technology is expanding in the field of organic synthesis [1][2][3][4][5]. The application of continuous-flow systems is frequently found in chemistry, and is beginning to have a significant impact on the way

• simplicity of designing and building flow reactors employing 3D-printing techniques allows for an easy and convenient integration of devices in a flow setup. Therefore it represents a very attractive way to design and build new continuous-flow rigs for organic synthesis. Results and Discussion Experimental

Flow photochemistry: Old light through new windows

• Jonathan P. Knowles,
• Luke D. Elliott and
• Kevin I. Booker-Milburn

Beilstein J. Org. Chem. 2012, 8, 2025–2052, doi:10.3762/bjoc.8.229

• -irradiation problems encountered with batch reactors. • As a continuous flow device is scale independent, a single reactor can in principle be used to process a few milligrams of substrate up to nearly a kilogram per day (see macroreactors). • Due to much shorter path lengths high concentration solutions can

• of bulk solutions, which combined with the extremely short lifetime of singlet oxygen means that lengthy irradiations are often required. These issues can be overcome through the use of continuous-flow chemistry: reactions performed in this manner have only a small amount of oxygenated solvent and

• nanoparticles can effectively produce singlet oxygen when irradiated with LEDs in the oxidative degradation of 1,3-diphenylisobenzofuran [40]. Photocatalytic reactions Photocatalytic reactions are an area in which continuous flow can be particularly advantageous due to the large surface-to-volume ratio ensuring

Combined bead polymerization and Cinchona organocatalyst immobilization by thiol–ene addition

• Kim A. Fredriksen,
• Tor E. Kristensen and
• Tore Hansen

Beilstein J. Org. Chem. 2012, 8, 1126–1133, doi:10.3762/bjoc.8.125

• enhanced activity and selectivity sometimes exhibited by such organocatalysts, especially under aqueous conditions [2]. Recently, the use of polymer-supported organocatalysts in continuous-flow systems has also surfaced in the literature, and their development is quickly gaining momentum [3][4][5

Aryl nitrile oxide cycloaddition reactions in the presence of pinacol boronic acid ester

• Sarah L. Harding,
• Sebastian M. Marcuccio and
• G. Paul Savage

Beilstein J. Org. Chem. 2012, 8, 606–612, doi:10.3762/bjoc.8.67

• ], and continuous-flow processes [3][4]. An important consideration when using these reactions for multistep syntheses is whether they are chemically compatible, without having to resort to protection/deprotection systems. For example, to generate a library of 3-bi(hetero)aryl isoxazoline analogues 3 a

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

• Magnus Rueping Teerawut Bootwicha Erli Sugiono Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany 10.3762/bjoc.8.32 Abstract The asymmetric organocatalytic hydrogenation of benzoxazines, quinolines, quinoxalines and 3H-indoles in continuous-flow

• incorporating inline analytical devices the progress of reactions can be monitored and analyzed in real time, allowing fast reaction screening and optimization [43][44][45][46][47][48][49][50][51][52][53][54][55]. Continuous flow microreactors have been applied to a number of standard transformations in organic

• 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

Continuous-flow hydration–condensation reaction: Synthesis of α,β-unsaturated ketones from alkynes and aldehydes by using a heterogeneous solid acid catalyst

• Magnus Rueping,
• Teerawut Bootwicha,
• Hannah Baars and
• Erli Sugiono

Beilstein J. Org. Chem. 2011, 7, 1680–1687, doi:10.3762/bjoc.7.198

• Magnus Rueping Teerawut Bootwicha Hannah Baars Erli Sugiono Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany 10.3762/bjoc.7.198 Abstract A simple, practical and efficient continuous-flow hydration–condensation protocol was developed for the synthesis

• reactor; green chemistry; heterogeneous catalysis, microwave; Introduction In recent years, the development of continuous-flow technologies has expanded considerably and has had a significant impact on modern organic synthetic chemistry. Continuous-flow processes offer advantages, such as operational

• hazardous chemicals [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Furthermore, continuous-flow technologies allow chemical processes to be easily and rapidly scaled up, either by changing the volume of the single reactor, by performing the reaction for an extended reaction

Continuous proline catalysis via leaching of solid proline

• Suzanne M. Opalka,
• Ashley R. Longstreet and
• D. Tyler McQuade

Beilstein J. Org. Chem. 2011, 7, 1671–1679, doi:10.3762/bjoc.7.197

• . Keywords: aminoxylation; flow chemistry; heterogeneous catalysis; packed-bed microreactor; proline/thiourea catalysis; Introduction Continuous flow chemistry [1][2][3], performed in small dimension tubing or channels, differs from batch chemistry in that mixing and heat transfer are significantly faster

• ]. With researchers becoming increasingly interested in developing continuous-flow processes, the rapid assessment of catalyst conditions necessary for potential synthetic routes requires a simple approach to deal with limited-solubility catalysts. We have both a long-standing interest in the production

• , use and management of solids [30][31][32][33] and reactions [34][35] in flow as well as in proline catalysis [36][37]. This prompted us to consider new strategies for the implementation of proline in a continuous-flow system without resorting to proline analogues or tethered catalysts [38][39][40

The application of a monolithic triphenylphosphine reagent for conducting Appel reactions in flow microreactors

• Kimberley A. Roper,
• Heiko Lange,
• Anastasios Polyzos,
• Malcolm B. Berry,
• Ian R. Baxendale and
• Steven V. Ley

Beilstein J. Org. Chem. 2011, 7, 1648–1655, doi:10.3762/bjoc.7.194

• beads related to the solvent employed. To circumvent some of the issues with bead-type supports, monoliths have been developed as replacements for use in continuous-flow synthesis. Monoliths are a single continuous piece of uniformly porous material prepared by precipitation polymerisation of a

• to remove, and extensive, time-consuming purification protocols are often needed in order to isolate the desired product in high purity. We envisioned that the use of an immobilised triphenylphosphine source in combination with continuous-flow technologies could circumvent this problem, allowing easy

• flow characteristics of beads make these techniques undesirable for application in a continuous-flow setup, and the relatively high cost of these reagents limits their widespread use in common laboratory practices. It is particularly interesting that these past investigations have noted an increase in

Continuous-flow enantioselective α-aminoxylation of aldehydes catalyzed by a polystyrene-immobilized hydroxyproline

• Xacobe C. Cambeiro,
• Rafael Martín-Rapún,
• Pedro O. Miranda,
• Sonia Sayalero,
• Esther Alza,
• Patricia Llanes and
• Miquel A. Pericàs

Beilstein J. Org. Chem. 2011, 7, 1486–1493, doi:10.3762/bjoc.7.172

• Franqués, 1. E-08028, Barcelona, Spain 10.3762/bjoc.7.172 Abstract The application of polystyrene-immobilized proline-based catalysts in packed-bed reactors for the continuous-flow, direct, enantioselective α-aminoxylation of aldehydes is described. The system allows the easy preparation of a series of β

• -aminoxy alcohols (after a reductive workup) with excellent optical purity and with an effective catalyst loading of ca. 2.5% (four-fold reduction compared to the batch process) working at residence times of ca. 5 min. Keywords: α-aminoxylation; continuous flow; packed-bed reactors; polystyrene

• alternative for improving the productivity of catalytic species results from the implementation of heterogenized catalysts in continuous-flow reactors. Flow chemistry has experienced a very important development in the last ten years as an emerging technology for organic synthesis [51][52][53][54][55][56][57

Coupled chemo(enzymatic) reactions in continuous flow

• Ruslan Yuryev,
• Simon Strompen and
• Andreas Liese

Beilstein J. Org. Chem. 2011, 7, 1449–1467, doi:10.3762/bjoc.7.169

• Ruslan Yuryev Simon Strompen Andreas Liese Institute of Technical Biocatalysis, Hamburg University of Technology, Denickestr. 15, 21073, Hamburg, Germany 10.3762/bjoc.7.169 Abstract This review highlights the state of the art in the field of coupled chemo(enzymatic) reactions in continuous flow

• . Three different approaches to such reaction systems are presented herein and discussed in view of their advantages and disadvantages as well as trends for their future development. Keywords: biocatalysis; chemo-enzymatic reaction sequences; continuous flow; coupled reactions; reaction cascades

• ][10][11]. Biotransformations, which combine both of the biological principles mentioned, may be regarded as “single-reaction–single-enzyme continuous-flow” systems and classified as second-generation enzymatic processes (Figure 2, II). Such biotransformations naturally evolve from the corresponding

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

• employed. To demonstrate the advantages associated with microreaction technology a series of SNAr reactions were performed under continuous flow by following previously developed microwave protocols as a starting point for the investigation. By this approach, an automated microreaction platform (Labtrix

• ® 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

• for efficient heat transfer are required if costs are to be reduced, particularly at the production level. Looking towards another emerging technology, that of continuous-flow methodology, Kappe and coworkers [21] and Ryu et al. [22] demonstrated that the “microwave effect” can be mimicked in high