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

Efficient and selective chemical transformations under flow conditions: The combination of supported catalysts and supercritical fluids

• M. Isabel Burguete,
• Eduardo García-Verdugo and
• Santiago V. Luis

Beilstein J. Org. Chem. 2011, 7, 1347–1359, doi:10.3762/bjoc.7.159

• on solid supports or in liquid phases and supercritical fluids (scFs), to develop selective and enantioselective chemical transformations under continuous and semi-continuous flow conditions. The results presented have been selected to highlight how the combined use of those two elements can

• to a limited number of fields, a significant development in this area can be envisaged for the near future due to the clear advantages of these systems over the conventional ones. Keywords: biphasic systems; continuous flow processes; enantioselective catalysis; immobilized catalysts; polymer

• economic efficiency and in short time frames [1]. The use of flow systems clearly offers a simple approach towards addressing these last few issues. The main advantages of continuous flow systems using conventional or neoteric solvents have been highlighted in different books and reviews [2][3][4][5][6][7

Koch–Haaf reaction of adamantanols in an acid-tolerant hastelloy-made microreactor

• Takahide Fukuyama,
• Yu Mukai and
• Ilhyong Ryu

Beilstein J. Org. Chem. 2011, 7, 1288–1293, doi:10.3762/bjoc.7.149

• : continuous flow system; hastelloy; Koch–Haaf reaction; microreactor; Introduction The recent evolution of microreactor technology has allowed synthetic chemists to use this precisely sophisticated reaction apparatus in place of the well-established glassware batch flask [1][2][3][4][5][6][7][8][9][10

• % total yield (2c:2c':2c'' = 23:53:24). The batch reaction resulted in an inferior yield with more of the rearranged products (83% yield, 2c:2c':2c'' = 19:62:19). All results are summarized in Table 1. Multigram scale synthesis of 2a from 1a was carried out in a continuous flow reaction. When the reaction

The Eschenmoser coupling reaction under continuous-flow conditions

• Sukhdeep Singh,
• J. Michael Köhler,
• Andreas Schober and
• G. Alexander Groß

Beilstein J. Org. Chem. 2011, 7, 1164–1172, doi:10.3762/bjoc.7.135

Triple-channel microreactor for biphasic gas–liquid reactions: Photosensitized oxygenations

• Ram Awatar Maurya,
• Chan Pil Park and
• Dong-Pyo Kim

Beilstein J. Org. Chem. 2011, 7, 1158–1163, doi:10.3762/bjoc.7.134

• context triple-channel microreactors could be quite useful as they comprise all the required elements for photosensitized oxygenations, namely continuous-flow processing, large gas–liquid interfacial area, short molecular diffusion distances, and very high surface illumination homogeneity. The middle

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

• , respectively. Under optimal reaction conditions the quantity of product could be increased from 31 mg per hour to 340 mg per hour simply by changing the volumetric capacity of the monolith. Keywords: continuous flow; microwave heating; monolith; scaling-up; Suzuki–Miyaura reaction; Introduction Interest in

• ][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

• [12][13]. To this end, the use of microwave heating in conjunction with microporous monolithic reactors has attracted some interest for small-scale synthesis under continuous-flow conditions [14][15][16]. One obvious problem, however, when using microwaves to heat solvents/reagents and surface

Evaluation of a commercial packed bed flow hydrogenator for reaction screening, optimization, and synthesis

• Marian C. Bryan,
• David Wernick,
• Christopher D. Hein,
• James V. Petersen,
• John W. Eschelbach and
• Elizabeth M. Doherty

Beilstein J. Org. Chem. 2011, 7, 1141–1149, doi:10.3762/bjoc.7.132

• H-Cube® and the effect of that dispersion on the reaction outcome [15]. As a result of that study, we generated a predictive correlation between non-steady state and continuous flow scale-up conditions for simple reductions. In this report, using the reduction of styrene to ethylbenzene over 10% Pd

• (Figure 7). It should be noted that Kappe observed a “Pd mirror” due to soluble Pd leaching from a CatCart® during a continuous flow Mizorki–Heck reaction [24]. In comparison, the fine black precipitate seen in our wash experiment is more consistent with solid Pd/C catalyst. The experiment was repeated

Continuous flow photolysis of aryl azides: Preparation of 3H-azepinones

• Farhan R. Bou-Hamdan,
• François Lévesque,
• Alexander G. O'Brien and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2011, 7, 1124–1129, doi:10.3762/bjoc.7.129

• Berlin, Germany 10.3762/bjoc.7.129 Abstract Photolysis of aryl azides to give nitrenes, and their subsequent rearrangement in the presence of water to give 3H-azepinones, is performed in continuous flow in a photoreactor constructed of fluorinated ethylene polymer (FEP) tubing. Fine tuning of the

• reaction conditions using the flow reactor allowed minimization of secondary photochemical reactions. Keywords: azepinones; azides; continuous flow; nitrenes; photochemistry; Findings Although photochemical rearrangements are an important class of reactions for heterocycle synthesis [1][2], their use is

• often hindered by technical difficulties, both in research laboratories and in industry, particularly when large quantities of material are required [3][4]. In response, there has been a recent growth in the application of continuous flow techniques [5][6][7] for the deployment of photochemical

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

• : continuous flow reactions; fluorine; fluoropyrazole; gas-liquid flow reactor; selective direct fluorination; Introduction Organic systems which bear fluorine atoms are used in an ever widening range of applications in the life sciences. Many commercially significant pharmaceutical and agrochemical products

• 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

• established that, in both batch and continuous flow processes, 1,3-dicarbonyl derivatives are not equally reactive towards fluorine gas [12] and that the ease of selective direct fluorination depends on the nature and proximity of other functional groups. Substrates that have a high initial equilibrium enol

Chemistry in flow systems II

• Andreas Kirschning

Beilstein J. Org. Chem. 2011, 7, 1046–1047, doi:10.3762/bjoc.7.119

• promising results, and the lasting effects will certainly become apparent in the years to come. I am very pleased to say that this series contains representative examples of fields in organic synthesis where continuous flow conditions have already made a significant impact. In particular I would like to

Continuous flow hydrogenation using polysilane-supported palladium/alumina hybrid catalysts

• Hidekazu Oyamada,
• Takeshi Naito and
• Shū Kobayashi

Beilstein J. Org. Chem. 2011, 7, 735–739, doi:10.3762/bjoc.7.83

• Hidekazu Oyamada Takeshi Naito Shu Kobayashi Department of Chemistry, School of Science and Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan 10.3762/bjoc.7.83 Abstract Continuous flow systems for hydrogenation using polysilane-supported

• polymer-incarcerated (PI) catalysts, which have high catalytic activity without causing metal leaching [1]. Heterogeneous catalytic hydrogenation in a batch system has recently been applied to continuous flow hydrogenation systems for high-throughput synthesis [2][3][4][5][6][7][8][9][10]. There are

• of catalysts (or inability for their re-use), the need for vigorous stirring to achieve catalytic activity, and the possible necessity for longer reaction times, which may lead to undesirable side reactions or harsh reaction conditions. Continuous flow systems have the potential to overcome these

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

• explanations for these highly unusual rate accelerations are presented. In addition, general aspects of reactor degradation, corrosion and contamination effects of importance to continuous flow chemistry are discussed. Keywords: flow chemistry; heterogeneous catalysis; microreactors; palladium; process

• continuous flow processes is becoming increasingly important. In the past few years our research group [19][20][21][22][23][24][25] has reported a number of successful case studies where initial reaction optimization for a variety of synthetic transformations was performed under batch microwave conditions

Studies on Pd/NiFe₂O₄ catalyzed ligand-free Suzuki reaction in aqueous phase: synthesis of biaryls, terphenyls and polyaryls

• Sanjay R. Borhade and
• Suresh B. Waghmode

Beilstein J. Org. Chem. 2011, 7, 310–319, doi:10.3762/bjoc.7.41

• continuous flow of hydrogen gas [43]. The scanning electron microscope image shows that particle size of the catalyst is ~100 to 300 nm (Supporting Information File 1). The X-ray photoemission spectra confirms the formation of metallic Pd(0) particles, the binding energy values were 335.3 and 340.5 eV for Pd

About the activity and selectivity of less well-known metathesis catalysts during ADMET polymerizations

• Hatice Mutlu,
• Lucas Montero de Espinosa,
• Oĝuz Türünç and
• Michael A. R. Meier

Beilstein J. Org. Chem. 2010, 6, 1149–1158, doi:10.3762/bjoc.6.131

• from Radleys. Stirring was continued at the selected temperature under a continuous flow of nitrogen for 5 h. After 5 h reaction time, the reaction mixture was dissolved in 1 mL of THF and polymerization halted by the addition of 1 mL of ethyl vinyl ether. The mixture was then stirred for 30 min at

Self-assembly and semiconductivity of an oligothiophene supergelator

• Pampa Pratihar,
• Suhrit Ghosh,
• Vladimir Stepanenko,
• Sameer Patwardhan,
• Ferdinand C. Grozema,
• Laurens D. A. Siebbeles and
• Frank Würthner

Beilstein J. Org. Chem. 2010, 6, 1070–1078, doi:10.3762/bjoc.6.122

• , and then cooled to 0 °C in an ice-bath. To this solution, a solution of 2, 2´-bithiophene in dry THF (68.0 mg in 5 mL) was added dropwise under continuous flow of argon. A white solid precipitate was formed. The reaction mixture was stirred at room temperature for 1 h and then immersed in an ice-bath

• product was dissolved in 20 mL dry DMF, compound 9 added and the flask evacuated, purged three times with argon and ~15 mg of the Pd-catalyst added under continuous flow of argon. The reaction mixture was then heated at 80 °C for 8 h under an argon atmosphere. It was observed that an orange precipitate

Kinetics and mechanism of vanadium catalysed asymmetric cyanohydrin synthesis in propylene carbonate

• Michael North and
• Marta Omedes-Pujol

Beilstein J. Org. Chem. 2010, 6, 1043–1055, doi:10.3762/bjoc.6.119

• achieved at atmospheric pressure and room temperature [74][75][76][77], or in a gas-phase continuous flow reactor [78], thus facilitating the use of waste carbon dioxide in this process [79]. In this paper we give full details of the use of catalyst 2 in propylene carbonate, and describe kinetic studies

Continuous flow enantioselective arylation of aldehydes with ArZnEt using triarylboroxins as the ultimate source of aryl groups

• Julien Rolland,
• Xacobe C. Cambeiro,
• Carles Rodríguez-Escrich and
• Miquel A. Pericàs

Beilstein J. Org. Chem. 2009, 5, No. 56, doi:10.3762/bjoc.5.56

• : asymmetric synthesis; continuous flow; diarylmethanols; solid-supported catalyst; triarylboroxins; Introduction Diarylmethanols constitute the basic scaffold in several important drugs such as antihistamines and muscle relaxants (R)-neobenodine, (R)-orphenadrine or (S)-carbinoxamine (Figure 1) [1]. Despite

• -pass, continuous flow highly enantioselective ethylation of aldehydes characterized by very short residence times (down to 2.8 min) [23]. According to these precedents, we considered that 2 could be a good candidate for a planned continuous enantioselective production of diarylmethanols. When a large

• continuous flow enantioselective processes [52] are still scarce [22][53][54][55][56][57] in spite of the enormous potential of this methodology. Herein, we report the development of a continuous flow system for the preparation of enantioenriched diarylmethanols using triarylboroxins as the ultimate aryl

Acid- mediated reactions under microfluidic conditions: A new strategy for practical synthesis of biofunctional natural products

• Katsunori Tanaka and
• Koichi Fukase

Beilstein J. Org. Chem. 2009, 5, No. 40, doi:10.3762/bjoc.5.40

• prominent biological activity in a “practical” and a “industrial” manner. Keywords: acid-mediated reaction; microreactor; natural products synthesis; oligosaccharide; pristane; Introduction A continuous flow microreactor, an innovative technology, has been used to realize efficient mixing and fast heat

• problems, we used a continuous flow microreactor. An application of the microfluidic system to the glycosylation reaction was first reported by Seeberger and co-workers on α-mannosylation [18]. We also have established an efficient microfluidic glycosylation in combination with the affinity separation

• the synthetic procedure, therefore, we used a continuous flow microreactor. Optimal conditions for reductive opening of 4,6-O-benzylidene acetals by a microfluidic system, similar to the α-sialylation and the β-mannosylation protocols, were examined using the glucose 4,6-O-benzylidene acetal 7 (Table

Gold film- catalysed benzannulation by Microwave- Assisted, Continuous Flow Organic Synthesis (MACOS)

• Gjergji Shore,
• Michael Tsimerman and
• Michael G. Organ

Beilstein J. Org. Chem. 2009, 5, No. 35, doi:10.3762/bjoc.5.35

• of gold, copper, silver, and gold-on-silver were prepared and evaluated for their catalytic activity in the microwave-assisted, continuous flow benzannulation of aryl, alkyl and silylalkynes with alkynylbenzaldehydes. Only the gold-on-silver films possessed both the high level of catalytic activity

Radical carbonylations using a continuous microflow system

• Takahide Fukuyama,
• Md. Taifur Rahman,
• Naoya Kamata and
• Ilhyong Ryu

Beilstein J. Org. Chem. 2009, 5, No. 34, doi:10.3762/bjoc.5.34

• pressurized carbon monoxide gas. Good to excellent yields of carbonylated products were obtained via radical formylation, carbonylative cyclization and three-component coupling reactions, using tributyltin hydride or TTMSS as a radical mediator. Keywords: continuous flow system; microreactor; radical