Publications abstracts

    To date, the Vapourtec R-Series system has featured in 550 or more peer reviewed publications.
    Use the filter tools to see the sort of things that are possible, but note that most published papers will require a journal subscription.

    Practical and regioselective amination of arenes using alkyl amines

    Alessandro Ruffoni 1, Fabio Juliá 1, Thomas D. Svejstrup 1, Alastair J. McMillan 1, James J. Douglas 2, Daniele Leonori 1

    • a School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS, UK
    • b Department of Mechanical Engineering, Imperial College London, Exhibition Road, South Kensington Campus, London, SW7 2AZ, UK
    • c Department of Chemical Engineering, Loughborough University, Loughborough, UK

    The formation of carbon–nitrogen bonds for the preparation of aromatic amines is among the top five reactions carried out globally for the production of high-value materials, ranging from from bulk chemicals to pharmaceuticals and polymers. As a result of this ubiquity and diversity, methods for their preparation impact the full spectrum of chemical syntheses in academia and industry. In general, these molecules are assembled through the stepwise introduction of a reactivity handle in place of an aromatic C–H bond (that is, a nitro group, halogen or boronic acid) and a subsequent functionalization or cross-coupling. Here we show that aromatic amines can be constructed by direct reaction of arenes and alkyl amines using photocatalysis, without the need for pre-functionalization. The process enables the easy preparation of advanced building blocks, tolerates a broad range of functionalities, and multigram scale can be achieved via a batch-to-flow protocol. The merit of this strategy as a late-stage functionalization platform has been demonstrated by the modification of several drugs, agrochemicals, peptides, chiral catalysts, polymers and organometallic complexes.

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    The Influence of Residence Time Distribution on Continuous-Flow Polymerization

    Marcus H. Reis, Travis P. Varner, Frank A. Leibfarth

    • Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

    Continuous-flow chemistry is emerging as an enabling technology for the synthesis of precise polymers. Despite recent advances in this rapidly growing field, there remains a need for a fundamental understanding of how fluid dynamics in tubular reactors influence polymerizations. Herein, we report a comprehensive study of how laminar flow influences polymer structure and composition. Tracer experiments coupled with in-line UV-vis spectroscopy demonstrate how viscosity, tubing diameter, and reaction time affect the residence time distribution (RTD) of fluid in reactor geometries relevant for continuous-flow polymerizations. We found that the breadth of the RTD has strong, statistical correlations with reaction conversion, polymer molar mass, and dispersity for polymerizations conducted in continuous flow. These correlations were demonstrated to be general to a variety of different reaction conditions, monomers, and polymerization mechanisms. Additionally, these findings inspired the design of a droplet flow reactor that minimizes the RTD in continuous-flow polymerizations and enables the continuous production of well-defined polymer at a rate of 1.4 kg/day.

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    Additive manufacturing of photoactive polymers for visible light harvesting

    Adilet Zhakeyevac, John Tobina, Huizhi Wangb, Filipe Vilelaa, Jin Xuanac

    • a School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS, UK
    • b Department of Mechanical Engineering, Imperial College London, Exhibition Road, South Kensington Campus, London, SW7 2AZ, UK
    • c Department of Chemical Engineering, Loughborough University, Loughborough, UK

    In recent years, 3D printing has gained a great deal of attention in the energy field, with numerous reports demonstrating its application in fabrication of electrochemical devices. The near-complete freedom of design offered by 3D printing technologies make them very appealing, since complex 3D parts can be directly fabricated. However, its application in photochemistry and solar energy harvesting remains, so far, an uncharted territory. In this work, a photoactive monomer was incorporated into commercially available 3D printing resin, which was subsequently used to successfully fabricate 3D photosensitizing structures for singlet oxygen generation. Results indicate that the SLA fabricated small-scale (0.1 ml) photoactive continuous flow reactor shows activity in singlet oxygen synthesis reaction under visible light irradiation (420 nm).

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    Modeling and Design of a Flow-Microreactor-Based Process for Synthesizing Ionic Liquids

    • Yuichi Nakahara *†⊥
    • Bert Metten
    • Osamu Tonomura §⊥
    • Aiichiro Nagaki ∥⊥
    • Shinji Hasebe §⊥
    • Jun-ichi Yoshida ⊥#
    • Francesco Molinari 1
    • New Frontiers Research Group, Frontier Research Laboratories, Institute For Innovation, Ajinomoto Co., Inc., 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki, Kanagawa 210-8681, Japan
    • Ajinomoto Bio Pharma Services, Cooppallaan 91, B-9230 Wetteren, Belgium
    • § Department of Chemical Engineering, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto 615-8510, Japan
    • Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto 615-8510, Japan
    • Micro Chemical Production Study Consortium in Kyoto University, Kyoto University, Nishikyo-ku, Kyoto 615-8510, Japan
    • # National Institute of Technology, Suzuka College, Shiroko-cho, Suzuka, Mie 510-0294, Japan

    A synthesis process for the ionic liquid (IL) 1-butyl-3-methylimidazolium chloride (BMIM.Cl) was developed using a flow microreactor (FMR) in this study. After the reaction rate analysis, the FMR was efficiently designed using computational fluid dynamics simulation, which can shorten the process development time by reducing trial-and-error experimentation. The designed FMR is composed of a V-shaped mixer and a tubular reactor having a millimeter-scale inner diameter. From the viewpoint of process operation and control, reactors with larger inner diameter are basically preferable. The influence of three inner diameters, 0.75, 2.16, and 4.35 mm, that satisfy temperature constraints on product quality, product yield, and production volume was investigated. It was found that as the inner diameter becomes large, the product yield becomes low because the mass transfer approaches the rate-limiting step of the reaction process. To avoid this problem, it was proposed that static mixers should be built in the reactor having the inner diameter of 4.35 mm. As a result, its production volume, without lowering the product yield, could be improved about 39 times compared with the conventional one.

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    Synthesis of a Renewable Macrocyclic Musk: Evaluation of Batch, Microwave, and Continuous Flow Strategies

    • Émilie Morin §
    • Johann Sosoe §
    • Michaël Raymond §
    • Benjamin Amorelli †*
    • Richard M. Boden
    • Shawn K. Collins
    • § Department of Chemistry and Centre for Green Chemistry and Catalysis, Université de Montréal, CP 6128 Station Downtown, Montréal, Québec, Canada H3C 3J7
    • Research & Development, International Flavors & Fragrances Inc., 1515 State Route 36, Union Beach, New Jersey, 07735, United States

    The renewable macrocyclic musk 3-methylcyclohexadec-6-enone was prepared via macrocyclic olefin metathesis on gram scale using two different protocols: a room temperature batch process which afforded a 57% yield of the desired macrocycle, but required long reaction times (5 d). In contrast, a continuous flow strategy provided a lower yield of 32% of macrocycle, although the short reaction times (150 °C, 5 min) improve throughput (1 g/4.8 h). Batch and continuous flow protocols were also tested on other macrocyclizations involving substrates bearing trisubstituted olefins.

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    Bioprocess Intensification Using Flow Reactors: Stereoselective Oxidation of Achiral 1,3-diols with Immobilized Acetobacter Aceti

    Valerio De Vitis 1, Federica Dall’Oglio 2, Francesca Tentori 3, Martina Letizia Contente 4, Elisabetta Brenna 3, Lucia Tamborini 2, Francesco Molinari 1

    • 1 Department of Food, Environmental and Nutritional Sciences (DeFENS), Università degli Studi di Milano, Via Celoria 2, 20133 Milan, Italy
    • 2 Department of Pharmaceutical Sciences (DISFARM), Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy
    • 3 Dipartimento di Chimica, Materiali ed Ingegneria Chimica “Giulio Natta” Politecnico di Milano, Via Mancinelli 7, I-20131 Milan, Italy
    • 4 School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK

    Enantiomerically enriched 2-hydroxymethylalkanoic acids were prepared by oxidative desymmetrisation of achiral 1,3-diols using immobilized cells of Acetobacter aceti in water at 28 °C. The biotransformations were first performed in batch mode with cells immobilized in dry alginate, furnishing the desired products with high molar conversion and reaction times ranging from 2 to 6 h. The biocatalytic process was intensified using a multiphasic flow reactor, where a segmented gas–liquid flow regime was applied for achieving an efficient O2-liquid transfer; the continuous flow systems allowed for high yields and high biocatalyst productivity.

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    Reversible chemoselective transetherification of vinylogous esters using Fe-catalyst under additive free conditions

    Nenavath Parvathalu, Sandip G. Agalave, Nirmala Mohanta and Boopathy Gnanaprakasam

    • Department of Chemistry, Indian Institute of Science Education and Research, Pune-411008, India

    An additive/Brønsted acid/base free, highly efficient and chemoselective transetherification of electron deficient vinylogous esters and water mediated de-alkylation using an earth-abundant Fe-catalyst under very mild reaction conditions is described. This reaction is highly selective to primary alcohols over secondary alcohols, has good functional group tolerance, is scalable to gram scale and a purification free sequential transetherification in a continuous flow mode is demonstrated.

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    Investigation of a Weak Temperature–Rate Relationship in the Carbamoylation of a Barbituric Acid Pharmaceutical Intermediate

    • Alexander G. O’Brien *†
    • Yangmu Chloe Liu *†
    • Mark J. Hughes
    • John Jin Lim
    • Neil S. Hodnett
    • Nicholas Falco
    • GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States
    • GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom

    The rate of reaction between N,N′-dicyclohexylbarbituric acid 1 and ethyl 2-isocyanatoacetate 2 is invariant with temperature. Positive orders in each reactant and dissociation of triethylammonium salts of 1 and product 3 at elevated temperature indicate that reaction occurs via a catalytic mechanism where changes to the positions of equilibria negate changes in the rate of the turnover-limiting step. A model for the consumption of 1 in a flow reactor accurately predicted the outcome of a laboratory-scale multivariate study.

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    Rapid and Multigram Synthesis of Vinylogous Esters under Continuous Flow: An Access to Transetherification and Reverse Reaction of Vinylogous Esters

    • Nirmala Mohanta, Moreshwar B. Chaudhari, Naveen Kumar Digrawal, and Boopathy Gnanaprakasam
    • Department of Chemistry, Indian Institute of Science Education and Research, Pune 411008, India

    An environmentally benign approach for the synthesis of vinylogous esters from 1,3-diketone and its reverse reaction under continuous-flow has been developed with alcohols in the presence of inexpensive Amberlyst-15 as a catalyst. This methodology is highly selective and general for a range of cyclic 1,3-dicarbonyl compounds which gives a library of linear alkylated and arylated vinylogous esters in good to excellent yield under solvent and metal free condition. Furthermore, the long-time experiment in a continuous-flow up to 40 h afforded 8.0 g of the vinylogous ester with turnover number (TON) = 28.6 and turnover frequency (TOF) = 0.715 h–1 using Amberlyst-15 as a catalyst. Furthermore, a continuous-flow sequential transetherification of vinylogous esters with various alcohols has been achieved in high yield. Reversibly, this vinylogous ester was deprotected or hydrolyzed into ketone using environmentally benign water as a solvent and Amberlyst-15 as a catalyst under continuous-flow process.

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    Protection‐Group‐Free Synthesis of Sequence‐Defined Macromolecules via Precision λ‐Orthogonal Photochemistry

    Waldemar Konrad, Christian Fengler, Sarrah Putwa, and Christopher Barner-Kowollik

    • Macromolecular Architectures, Institut für Technische Chemie und Polymerchemie, Karlsruhe Institute of Technology (KIT), Engesserstr. 18, 76131 Karlsruhe, Germany
    • School of Chemistry, Physics and Mechanical Engineering, Queensland University of Technology (QUT), 2 George Street, QLD, 4000 Brisbane, Australia

    An advanced light‐induced avenue to monodisperse sequence‐defined linear macromolecules via a unique photochemical protocol is presented that does not require any protection‐group chemistry. Starting from a symmetrical core unit, precision macromolecules with molecular weights up to 6257.10 g mol−1 are obtained via a two‐monomer system: a monomer unit carrying a pyrene functionalized visible light responsive tetrazole and a photo‐caged UV responsive diene, enabling an iterative approach for chain growth; and a monomer unit equipped with a carboxylic acid and a fumarate. Both light‐induced chain growth reactions are carried out in a λ‐orthogonal fashion, exciting the respective photosensitive group selectively and thus avoiding protecting chemistry. Characterization of each sequence‐defined chain (size‐exclusion chromatography (SEC), high‐resolution electrospray ionization mass spectrometry (ESI‐MS), and NMR spectroscopy), confirms the precision nature of the macromolecules.

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    Decarboxylative Intramolecular Arene Alkylation Using N-(Acyloxy)phthalimides, an Organic Photocatalyst, and Visible Light

    • Trevor C. Sherwood*†
    • Hai-Yun Xiao*†
    • Roshan G. Bhaskar
    • Eric M. Simmons
    • Serge Zaretsky
    • Martin P. Rauch§
    • Robert R. Knowles§
    • T. G. Murali Dhar
    • Research and Development, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, New Jersey 08543-4000, United States
    • Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States
    • §Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States

    An intramolecular arene alkylation reaction has been developed using the organic photocatalyst 4CzIPN, visible light, and N-(acyloxy)phthalimides as radical precursors. Reaction conditions were optimized via high-throughput experimentation, and electron-rich and electron-deficient arenes and heteroarenes are viable reaction substrates. This reaction enables access to a diverse set of fused, partially saturated cores which are of high interest in synthetic and medicinal chemistry.

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    Flow Electrochemical Cyclizations via Amidyl Radicals: Easy Access to Cyclic Ureas

    Nisar Ahmeda,b*, Aggeliki Vgenopouloua

    • a School of Chemistry, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
    • b School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK

    Flow chemistry has advantages over batch processes and can achieve the synthesis of substances in high yield under safe working conditions. The combination of electrochemistry and flow microreactor technology has made chemical transformations possible without the use of oxidants or catalysts. Herein, we report flow electrosynthesis of cyclic ureas via oxyamination of N-allylic ureas. We have found that continuous flow is able to outperform its batch counterpart, producing cyclic ureas in excellent yields.

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    Efficient Flow Electrochemical Alkoxylation of Pyrrolidine-1-Carbaldehyde

    Nasser Amria, Ryan A. Skiltonb, Duncan Guthrieb, Thomas Wirth*a

    • a School of Chemistry, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
    • b Vapourtec Ltd., 21 Park Farm Business Centre, Bury St Edmunds, IP28 6TS, UK

    We report on the optimization of the alkoxylation of pyrrolidine-1-carbaldehyde by using a new electrochemical microreactor. Precise control of the reaction conditions permits the synthesis of either mono- or dialkoxylated reaction products in high yields.

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    Overcoming Water Insolubility in Flow: Enantioselective Hydrolysis of Naproxen Ester

    David Roura Padrosa1 , Valerio De Vitis2 , Martina Letizia Contente1* , Francesco Molinari2, Francesca Paradisi1*

    • 1 School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
    • 2 Department of Food, Environmental and Nutritional Sciences (DeFENS), Università degli studi di Milano, Via Mongiagalli 25, 20133 Milan, Italy;

    Hydrolytic enantioselective cleavage of different racemic non-steroidal anti-inflammatory drugs (NSAIDs) ester derivatives has been studied. An engineered esterase form Bacillus subtilis (BS2m) significantly outperformed homologous enzymes from Halomonas elongata (HeE) and Bacillus coagulants (BCE) in the enantioselective hydrolysis of naproxen esters. Structural analysis of the three active sites highlighted key differences which explained the substrate preference. Immobilization of a chimeric BS2m-T4 lysozyme fusion (BS2mT4L1) was improved by resin screening achieving twice the recovered activity (22.1 ± 5 U/g) with respect to what had been previously reported, and was utilized in a packed bed reactor. Continuous hydrolysis of α-methyl benzene acetic acid butyl ester as a model substrate was easily achieved, albeit at low concentration (1 mM). However, the high degree of insolubility of the naproxen butyl ester resulted in a slurry which could not be efficiently bioconverted, despite the addition of co-solvents and lower substrate concentration (1 mM). Addition of Triton® X-100 to the substrate mix yielded 24% molar conversion and 80% e.e. at a 5 mM scale with 5 min residence time and sufficient retention of catalytic efficiency after 6 h of use.

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    A solid-supported arylboronic acid catalyst for direct amidation

    • Yihao Dua,
    • Thomas Barbera,
    • Sol Ee Lima,
    • Henry S. Rzepab,
    • Ian R. Baxendale*a,
    • Andrew Whiting*a,
    • a Centre for Sustainable Chemical Processes, Department of Chemistry, Durham University, Science Laboratories, South Road, Durham, UK
    • a Department of Chemistry, Imperial College, South Kensington Campus, London, UK

    An efficient heterogeneous amidation catalyst has been prepared by co-polymerisation of styrene, DVB with 4-styreneboronic acid, which shows wide substrate applicability and higher reactivity than the equivalent homogeneous phenylboronic acid, suggesting potential cooperative catalytic effects. The catalyst can be easily recovered and reused; suitable for use in packed bed flow reactors.

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    Visible Light‐Promoted Beckmann Rearrangements: Separating Sequential Photochemical and Thermal Phenomena in a Continuous Flow Reactor

    Yuesu Chen, David Cantillo, C. Oliver Kappe

    • Karl-Franzens-Universitat Graz, Institute of Chemistry, 8010 Graz, AUSTRIA

    The Beckmann rearrangement of oximes to amides typically requires strong acids or highly reactive, hazardous electrophiles and/or high tempertatures to proceed. A very attractive alternative is the in situ generation of Vilsmeier‐Haack reagents, by means of photoredox catalysis, as promoters for the thermal rearrangement. Investigation of the reaction parameters for this light induced method using a one‐pot strategy has shown that the reaction is limited by the different temperatures required for each of the two sequential steps. Using a continuous flow reactor, the photochemical and thermal processes have been separated by integrating a flow photoreactor unit at low temperature for the electrophile generation with a second reactor unit, at high temperature, where the rearrangement takes place. This strategy has enabled excellent conversions and yields for a diverse set of oximes, minimizing all side products that were being obtained with the original one‐pot method.

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    A Consolidated and Continuous Synthesis of Ciprofloxacin from a Vinylogous Cyclopropyl Amide

    • N. Perrer Tosso, Bimbisar K. Desai, Eliseu De Oliveira, Juekun Wen, John Tomlin, and B. Frank Gupton*
    • Department of Chemistry and Department of Chemical and Life Science Engineering, Virginia Commonwealth University, 601 West Main Street, Richmond, Virginia 23220, United States

    Ciprofloxacin is a broad-spectrum antibiotic that is recognized as one of the World Health Organization’s Essential Medicines. It is particularly effective in the treatment of Gram-negative bacterial infections associated with urinary, respiratory, and gastrointestinal tract infections. A streamlined and high yielding continuous synthesis of ciprofloxacin has been developed, which employs a chemoselective C-acylation step that precludes the need for intermediate isolations, extractions, or purifications. The end-to-end process has a residence time of 4.7 min with a 15.8 g/h throughput at laboratory scale and an overall isolated yield of 83%.

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    Emerging Trends in Flow Chemistry and Applications to the Pharmaceutical Industry

    Andrew R Bogdan and Amanda W Dombrowski

    • Discovery Chemistry and Technologies, AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States

    The field of flow chemistry has garnered considerable attention over the past two decades. This perspective highlights many recent advances in the field of flow chemistry and discusses applications to the pharmaceutical industry, from discovery to manufacturing. From a synthetic perspective, a number of new enabling technologies are providing more rationale to run reactions in flow over batch techniques. Additionally, highly automated flow synthesis platforms have been developed with broad applicability across the pharmaceutical industry, ranging advancing medicinal chemistry programs to self-optimizing synthetic routes. A combination of simplified and automated systems is discussed, demonstrating how flow chemistry solutions can be tailored to fit the specific needs of a project.

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    Towards a Scalable Synthesis of 2‐Oxabicyclo[2.2.0]hex‐5‐en‐3‐one Using Flow Photochemistry

    Jason D. Williamsa,b, Yuma Otakea, Guilhem Coussanesc, Iakovos Saridakiscc, Nuno Maulidecc, C. Oliver Kappeaa,b

    • a Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
    • b Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria
    • c Institute of Organic Chemistry, University of Vienna, Währinger Strasse 38, 1090 Vienna, Austria

    Cyclobutene lactones hold great potential as synthetic building blocks, yet their preparation by photochemical rearrangement in batch can often be a bottleneck in synthetic studies. We report the use of flow photochemistry as a tool to enable a higher‐throughput approach to the synthesis of 2‐oxabicyclo[2.2.0]hex‐5‐en‐3‐one, which reduces reaction times from 24 hours to 10 minutes. Accordingly, a significantly improved throughput of 144 mg/h (vs 14‐21 mg/h in batch) was achieved. Scale‐out experiments showed problematic reactor fouling, whereby steps were taken to explore and minimize this effect.

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    Continuous flow processing as a tool for the generation of terpene-derived monomer libraries

    Renan Galavernaa, Lucas P. Fernandesa, Duncan L. Browneb, Julio C. Pastrea

    • a Institute of Chemistry, University of Campinas – UNICAMP, Campinas, Brazil
    • b School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK

    We report the development of a continuous flow approach for the preparation of two bio-derived monomer libraries. A small range of terpenes (ocimene, myrcene, α-terpinene, α-phellandrene, isoprene, and farnesene) have been used as the base set for the library, with the first library derived from a Diels–Alder reaction with the platform chemical maleic anhydride. The second library requires the derivatization of the first through a hydrogenation reaction. The potential for scale-up of both libraries has been demonstrated, with the Diels–Alder process delivering 10.5 grams of the product in 3 hours and the hydrogenation process delivering 10 grams of the material in 16 hours.

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    Rapid Photochemical Reaction Studies under Continuous-flow Conditions in the Vapourtec UV-150 Reactor-A Technical Note

    Richard Huntera, Sam Joslanda, Joseph Mooreb, Duncan Guthrieb, Mark J. Robertsona, Michael Oelgemöllera

    • a College of Science and Engineering, James Cook University, Townsville, QLD 4911, Australia
    • b Vapourtec Ltd, Park Farm Business Centre, Fornham St Genevieve, Bury St Edmunds, Suffolk, IP28 6TS, UK

    Five different model reactions (photodecarboxylation, inter- and intramolecular [2+2] cycloadditions, TiO2 photocatalytic reduction and type II photooxygenation) were investigated in the advanced Vapourtec UV-150 photo reactor with their conversion and throughput potentials reported. Compared to known batch reactions in laboratory reactors, significantly higher calculated productivities were achieved despite a rather small 10 mL reactor coil. The device enables rapid, convenient, reliable and reproducible flow photochemistry studies across the entire wavelengths spectrum and on flexible scales.

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    Enabling synthesis in fragment-based drug discovery by reactivity mapping: photoredox-mediated cross-dehydrogenative heteroarylation of cyclic amines

    Rachel Grainger*a, Tom D. Heightmana, Steven V. Leyb, Fabio Limab,c, Christopher N. Johnson*a

    • a Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge, UK
    • b Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
    • c Novartis Pharma AG, Novartis Campus, 4002 Basel, Switzerland

    In fragment-based drug discovery (FBDD), a weakly binding fragment hit is elaborated into a potent ligand by bespoke functionalization along specific directions (growth vectors) from the fragment core in order to complement the 3D structure of the target protein. This structure-based design approach can present significant synthetic challenges, as growth vectors often originate on sp2 or sp3 ring carbons which are not the most synthetically accessible points on the fragment. To address this issue and expedite synthesis in FBDD, we established a nanogram-to-gram workflow for the development of enabling synthetic transformations, such as the direct C–H functionalization of heterocycles. This novel approach deploys high-throughput experimentation (HTE) in 1536-well microtiter plates (MTPs) facilitated by liquid handling robots to screen reaction conditions on the nanomolar scale; subsequently the reaction is upscaled in a continuous flow to generate gram-quantities of the material. In this paper, we disclose the use of this powerful workflow for the development of a photoredox-mediated cross-dehydrogenative coupling of fragments and medicinally relevant heterocyclic precursors via Minisci-type addition of α-amino radicals to electron-deficient heteroarenes. The optimized reaction conditions were employed on the milligram-scale on a diverse set of 112 substrates to map out structure–reactivity relationships (SRRs) of the transformation. The coupling exhibits excellent tolerance to a variety of functional groups and N-rich heteroarenes relevant to FBDD and was upscaled in a continuous flow to afford gram-quantities of pharmaceutically relevant sp2–sp3 privileged architectures.

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    Enhanced mixing of biphasic liquid-liquid systems for the synthesis of gem-dihalocyclopropanes using packed bed reactors

    T von Keutz1,2, D Cantillo1,2, CO Kappe1,2

    • 1 Center for Continuous Flow Synthesis and Processing (CCFLOW) Research Center Pharmaceutical Engineering GmbH (RCPE) Graz, Austria
    • 2 Institute of Chemistry, NAWI Graz, University of Graz, Graz, Austria

    A continuous flow procedure for the gem-dichlorocyclopropanation of alkenes has been developed. The method is based on the generation of dichlorocarbene utilizing the classical biphasic aqueous sodium hydroxide/chloroform system. This reaction typically requires vigorous stirring for several hours in batch for completion. Tarry materials precipitate due to partial polymerization of dichlorocarbene and the process is difficult to scale. To overcome these problems and achieve very efficient mixing during the flow process a column reactor packed with PTFE beads as inert filling material has been used. PTFE beads have been found to be the optimal material to obtain fine dispersions of the aqueous phase in the organic solution. By heating the packed-bed reactor at 80 °C excellent conversions have been achieved after a residence time of only 4 min. The process has been applied for the synthesis of Ciprofibrate, a dichlorocyclopropane-containing drug used as treatment for several diseases associated with high lipid content in blood.

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    Deprotection of N-Boc Groups Under Continuous Flow High Temperature Conditions

    • Bryan Li
    • Ruizhi Li
    • Peter Dorff
    • James Christopher McWilliams
    • Robert M Guinn
    • Steven M. Guinness
    • Lu Han
    • Ke Wang
    • Shu Yu
    • Medicinal Science, Worldwide Research and Development, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, United States

    The scope of thermolytic, N-Boc deprotection was studied on 26 compounds from the Pfizer compound library, representing a diverse set of structural moieties. Among these compounds, 12 substrates resulted in clean (≥95% product) deprotection, and an additional three compounds gave ≥90% product. The thermal de-Boc conditions were found to be compatible with a large number of functional groups. A combination of computational modeling, statistical analysis, and kinetic model fitting was used to support an initial, slow, and concerted proton transfer with release of isobutylene, followed by a rapid decarboxylation. A strong correlation was found to exist between the electrophilicity of the N-Boc carbonyl group and the reaction rate.

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    A Laser Driven Flow Chemistry Platform for Scaling Photochemical Reactions with Visible Light

    • Kaid C. Harper, Eric G. Moschetta, Shailendra V. Bordawekar, Steven J. Wittenberger
    • Process Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States

    Visible-light-promoted organic reactions can offer increased reactivity and selectivity via unique reaction pathways to address a multitude of practical synthetic problems, yet few practical solutions exist to employ these reactions for multikilogram production. We have developed a simple and versatile continuous stirred tank reactor (CSTR) equipped with a high-intensity laser to drive photochemical reactions at unprecedented rates in continuous flow, achieving kg/day throughput using a 100 mL reactor. Our approach to flow reactor design uses the Beer–Lambert law as a guideline to optimize catalyst concentration and reactor depth for maximum throughput. This laser CSTR platform coupled with the rationale for design can be applied to a breadth of photochemical reactions.

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    De novo design of organic photocatalysts: bithiophene derivatives for the visible‐light induced C‐H functionalization of heteroarenes

    • Cecilia Bottecchia1
    • Raul Martin2
    • Irini Abdiaj3
    • Ettore Crovini4
    • Jesus Alcazar3
    • Jesus Jorduna
    • Maria Blesa
    • Jose Carrillo3
    • Pilar Prieto
    • Timothy Noel1
    • 1 TU Eindhoven, Netherlands
    • 2 Universidad de Castilla-La Mancha Facultad de Ciencias y Tecnologias Quimicas de Ciudad Real, Spain
    • 3 Janssen Research and Development, Spain
    • 4 University of Saint Andrews School of Chemistry, United Kingdom

    Herein, we report the de novo synthesis and characterization of a series of substituted bithiophene derivatives as novel and inexpensive organic photocatalysts. DFT calculations were used to predict a priori their absorption spectra and redox potentials, which were then confirmed with empirical data. The photocatalytic activity of this novel class of organic photoredox catalyst was demonstrated in two visible‐light mediated strategies for the C‐H functionalization of heteroarenes. The implementation of these strategies in a continuous‐flow photo‐microreactor afforded moderate to excellent yields within few minutes of reaction time. Due to their straightforward synthesis, low cost and good photocatalytic properties we believe that the proposed bithiophene derivatives could be employed as a new class of organic photoredox catalysts.

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    Integrating reactive distillation with continuous flow processing

    Marcus Baumann

    • School of Chemistry, University College Dublin, Science Centre South, Belfield, Dublin 4, Ireland

    A continuous flow process for the synthesis of trifluoromethylthioethers is reported. The palladium-catalyzed C-H trifluoromethylthiolation of amides derived from the 8-aminoquinoline using N-[(trifluoromethyl)thio]phthalimide produced the desired products in moderate to good yields with a residence time of 20 min. In comparison with the batch process, the reaction time was decreased by a factor of 100 to 200, demonstrating the positive effect of continuous flow processes for this type of reaction.

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    Enabling tools for continuous-flow biphasic liquid–liquid reaction

    Nopphon Weeranoppanant a

    • a Department of Chemical Engineering, Faculty of Engineering, Burapha University, 169 Longhard Bangsaen, Saensook, Muang, Thailand

    Flow chemistry has attracted considerable attention as it offers several advantages over conventional batch chemistry. Several multiphase reactions, including liquid–liquid reactions, are more efficient in flow due to intensified mass transfer. This observation has led to many developments of enabling tools in recent years. In this minireview, an up-to-date overview of such tools will be highlighted. In addition, interesting examples of the integrated continuous-flow process with liquid–liquid reactions will also be presented.

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    High-Throughput Template-Free Continuous Flow Synthesis of Polyaniline Nanofibers

    • Rekha Singh†#
    • Karuna Veeramani†‡#
    • Rishab Bajpai
    • Anil Kumar*†‡§
    • Department of Chemistry, IITB-Monash Research Academy,§ National Centre for Excellence in Technologies for Internal Security (NCETIS), Indian Institute of Technology Bombay, Powai, Mumbai, 400076, India

    The large-scale and high-throughput synthesis of conjugated polymer based nanofibers always remain a challenge for the chemists due to the issues related to secondary nucleation in traditional batch processes. Typically polyaniline (PANI) nanofibers are synthesized under highly dilute conditions resulting in a very low throughput of few hundred milligrams per hour and a low space-time yield (STY) of 1–2 g·L–1·h–1. In this manuscript, we report the continuous flow synthesis of PANI nanofibers which results in high throughput (17–30 g·h–1) and high space-time yield (140–450 g·L–1·h–1). These polyaniline nanofibers show high surface area (42 m2·g–1), high specific capacitance (577 F·g–1), and high crystallinity. Finally, the present method is generic in nature and, in principle, can be extended for the synthesis of nanofibers of other conjugated polymers via oxidative polymerization.

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    A Continuous Flow Strategy for the Facile Synthesis and Elaboration of Semi‐Saturated Heterobicyclic Fragments

    Nicola Luise, Eleanor Wyatt, Gary Tarver, Paul Graham Wyatt

    • University of Dundee, School of Life Sciences, DD1 5EH Dundee, UNITED KINGDOM

    An efficient hydrogenation protocol under continuous flow conditions was developed for the synthesis of underrepresented semi‐saturated bicyclic fragments containing highly sp3‐rich skeletons for fragment‐based drug discovery (FBDD) programs. Excellent yields were generally achieved by using Pd/C (10% w/w) and RaNi at 25‐150 °C under 4‐100 bar of hydrogen pressure. The generated fragments, with appropriate physicochemical properties, present diverse hydrogen‐bonding pharmacophores and useful vectors for their synthetic elaboration in the optimization stage. Successive, simple functionalizations in continuous flow were accomplished to demonstrate the opportunity to develop multi‐step continuous flow synthesis of valuable starting points for FBDD campaigns. A conclusive quality control (QC) was essential to discard those structures that do not fit typical fragment library parameters.

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    Continuous Flow Chlorination of Alkenyl Iodides Promoted by Copper Tubing

    Antoine Niteleta, Vanessa Kairouzb, Hélène Lebelb, André B. Charetteb, Gwilherm Evanoa,

    • a  Laboratoire de Chimie Organique, Service de Chimie et Physico, Chimie Organiques, Université libre de Bruxelles (ULB), Avenue F. D. Roosevelt 50, CP160/06, 1050 Brussels, Belgium
    • b  Centre in Green Chemistry and Catalysis, Faculty of Arts and Sciences, Department of Chemistry, Université de Montréal, P.O. Box 6128, Station Downtown, Montréal, Québec, H3C 3J7, Canada

    A simple continuous flow synthesis of alkenyl chlorides from the corresponding readily available alkenyl iodides in copper reactor tubing is described. A variety of alkenyl chlorides were obtained in good to excellent yields with full retention of the double bond geometry. The reaction time was reduced by a factor of 24–48 compared to the batch process.

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    Continuous flow palladium-catalyzed trifluoromethylthiolation of C-H bonds

    Alexanne Bouchard 1, Vanessa Kairouz 1, Maxime Manneveau 2, Heng-Ying Xiong 2, Tatiana Besset 2

    • 1 Department of Chemistry and Continuous Flow Synthesis Laboratory, Université de Montréal, Montréal, Canada
    • 2 INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), Normandie Université, Rouen, France

    A continuous flow process for the synthesis of trifluoromethylthioethers is reported. The palladium-catalyzed C-H trifluoromethylthiolation of amides derived from the 8-aminoquinoline using N-[(trifluoromethyl)thio]phthalimide produced the desired products in moderate to good yields with a residence time of 20 min. In comparison with the batch process, the reaction time was decreased by a factor of 100 to 200, demonstrating the positive effect of continuous flow processes for this type of reaction.

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    Continuous preparation for rifampicin

    Xin Li 1, Zhuang Liu 1, Zheng Fang 1, Hao Qi 1, Siyu Huang 1, Shanshan Miao 1, Kai Guo 1,2

    • 1 College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, China
    • 2 State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, China

    To reduce the cost and improve the efficiency for rifampicin preparation, a continuous flow synthesis of rifampicin starting from rifamycin S and tert-butylamine was studied in a microreactor. Two reaction steps and one purification step were coupled in a microreactor, and rifampicin was obtained with 67% overall yield. This method used 25% less 1-amino-4-methyl piperazine and got 16% higher overall yield without changing solvent and purification process between steps. This method has a good potential for further industrial application.

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    Using Carbon Dioxide as a Building Block in Continuous Flow Synthesis

    • Hyowon Seo
    • Long V. Nguyen
    • Timothy F. Jamison

      Carbon dioxide (CO2) is an attractive building block for organic synthesis that is environmentally friendly. Continuous flow technologies have enabled C−O and C−C bond forming reactions with CO2 that previously were either low‐yielding or impossible in batch to afford value‐added chemicals. This review describes recent advances in continuous flow as an enabling strategy in utilizing CO2 as a C1 building block in chemical synthesis.

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      Chemoselective Synthesis of Amines from Ammonium Hydroxide and Hydroxylamine in Continuous Flow

      • Clément Audubert
      • Alexanne Bouchard
      • Gary Mathieu
      • Hélène Lebel
      • Department of Chemistry and Centre in Green Chemistry and Catalysis (CGCC), Université de Montréal, P.O. Box 6128, Station Downtown, Montréal, QC H3C 3J7, Canada

      The chemoselective amination of alkyl bromides and chlorides with aqueous ammonia and hydroxylamine was achieved in continuous flow to produce primary ammonium salts and hydroxylamines in high yields. An in-line workup was designed to isolate the corresponding primary amine, which was also telescoped in further reactions, such as acylation and Paal–Knorr pyrrole synthesis. Monosubstituted epoxides are also compatible with the reaction conditions.

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      Enantiospecific cyclization of methyl N-(tert-butoxycarbonyl)-N-(3-chloropropyl)-D-alaninate to 2-methylproline derivative via ‘memory of chirality’ in flow

      • Gianvito Vilé 1
      • Gunther Schmidt 2
      • Sylvia Richard-Bildstein 1
      • Stefan Abele 2
      • 1 Drug Discovery Chemistry, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland
      • 2 Chemical Development, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland

      We report for the very first time a continuous-flow route to perform the intramolecular cyclization of haloalkyl-substituted α-amino esters via memory of chirality (MoC), using lithium bis(trimethylsilyl)amine as a base and methyl N-(tert-butoxycarbonyl)-N-(3-chloropropyl)-D-alaninate as a model reactant. The various reaction parameters, such as temperature, residence time, reactant stoichiometry, or type and concentration of the base were optimized to maximize the yield of the cyclized product and its enantiomeric excess. At the conditions identified, the reaction was eventually scaled up, reaching a productivity of 11 g h−1. Compared to the standard batch protocols available in the literature, the use of a microreactor enables a better control of the exothermicity associated with the addition of the organolithium reagent to the reaction mixture, resulting in operations at more practical temperatures, with high enantiospecificity and full conversion of the reactive amino ester within a few seconds of residence time.

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      Mg-Catalyzed OPPenauer Oxidation—Application to the Flow Synthesis of a Natural Pheromone

      • Virginie Liautard
      • Mélodie Birepinte
      • Camille Bettoli
      • Mathieu Pucheault

      The so-called OPPenauer oxidation is well known for its ability to oxidize valuable alcohols into their corresponding aldehydes or ketones. In particular, it has proven to be extremely successful in the oxidation of sterols. On the other hand, its application—in the original formulation—to the obtainment of ketones outside the field of steroids met a more limited success because of less favorable thermodynamics and side reactions. To circumvent these issues, the first example of magnesium-catalyzed OPPenauer oxidation is described. The oxidation of primary and secondary alcohol was performed using pivaldehyde or bromaldehyde as the oxidant and cheap magnesium tert-butoxide as catalyst. Decent to excellent yields were obtained using reasonable catalytic charge. The synthesis of a pheromone stemming from the Rhynchophorus ferrugineus was obtained by tandem addition-oxidation of 2-methylpentanal and the process was successfully applied to continuous flow on a multigram scale.

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      Dehydration of an Insoluble Urea Byproduct Enables the Condensation of DCC and Malonic Acid in Flow

      • Alexander G. O’Brien
      • Eric M. Ricci
      • Michel Journet
      • GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States

      A procedure for the preparation of N,N′-dicyclohexylbarbituric acid from DCC and malonic acid is described. Addition of phosphorus oxychloride to the reaction mixture facilitates dehydration of the insoluble byproduct N,N′-dicyclohexyl urea, enabling operation in continuous flow. A development approach based on in situ monitoring of batch reactions was used, which supported screening and determination of reaction conditions at small scale prior to scaleup in flow. Additional mechanistic understanding and control of impurity formation are presented.

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      Self-Sufficient Flow-Biocatalysis by Coimmobilization of Pyridoxal 5′-Phosphate and ω-Transaminases onto Porous Carriers

      • Ana I. Benítez-Mateos
      • Martina L. Contente §
      • Susana Velasco-Lozano
      • Francesca Paradisi
      • Fernando López-Gallego *⊥‡
      • Heterogeneous Biocatalysis Laboratory, CICbiomaGUNE, Paseo Miramón 182, Edificio empresarial C”, 20014 San Sebastián, Spain
      • § School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, U.K
      • Heterogeneous biocatalysis laboratory, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH−CSIC), University of Zaragoza, C/Pedro Cerbuna 12, 50009 Zaragoza, Spain
      • ARAID, Aragon I+D foundation, Zaragoza, Spain

      We expanded the application of self-sufficient heterogeneous biocatalysts containing coimmobilized ω-transaminases and pyridoxal 5′-phosphate (PLP) to efficiently operate packed-bed reactors in continuous flow. Using a ω-transaminase from Halomonas elongata coimmobilized with PLP onto porous methacrylate-based carriers coated with polyethylenimine, we operated a packed-bed reactor continuously for up to 50 column volumes at 1.45 mL × min–1 in the enantioselective deamination of model amines (α-methylbenzyl amine), yielding >90% conversion in all cycles without exogenous addition of cofactor. In this work, we expanded the concept of self-sufficient heterogeneous biocatalysts to other ω-transaminases such as the ones from Chromobacterium violaceum and Pseudomonas fluorescens. We found that enzymes with lower affinities toward PLP present lower operational stabilities in flow, even when coimmobilizing PLP. Furthermore, ω-transaminases coimmobilized with PLP were successfully implemented for the continuous synthesis of amines and the sustainable metrics were assessed. These results give some clues to exploit PLP-dependent ω-transaminases under industrially relevant continuous operations in a more cost-effective and environmentally friendly process.

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      A Convergent Continuous Multistep Process for the Preparation of C4-Oxime-Substituted Thiazoles

      • Edouard Godineau *†
      • Claudio Battilocchio †‡
      • Matthias Lehmann
      • Steven V. Ley
      • Ricardo Labes
      • Letitia Birnoschi
      • Srinivas Subramanian §
      • C.S Prasanna §
      • Amol Gorde §
      • Mahesh Kalbagh §
      • Vivek Khade §
      • Anton Scherrer
      • Anthony C. O’Sullivan
      • Syngenta Crop Protection, Process Research, Schaffhauserstrasse 101, CH-4332, Switzerland
      • Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, UK
      • § Syngenta Research and Technology Centre, Santa Monica Works, Corlim, Goa India, 403110

      We report a strategy designed for the rapid and convergent assembly of C4-oxime substituted thiazoles. Our approach relied on 3-bromo-2-oxopropanal O-methyl oxime 7 as a key building block. A three-step sequence to 7 was designed, which, for safety concerns, could only be operated in batch mode on limited scales (≪100 g). We describe herein how we addressed such a limitation, by designing a multistep continuous synthesis of this intermediate and further demonstrate the advantages of flow reactor configuration upon scaling up.

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      Additive Free Fe-Catalyzed Conversion of Nitro to Aldehyde under Continuous Flow Module

      • Sandip G. Agalave
      • Moreshwar B. Chaudhari
      • Girish Singh Bisht
      • Boopathy Gnanaprakasam*
      • Department of Chemistry, Indian Institute of Science Education and Research Pune-411008, India

      Fe-catalyzed direct transformation of nitro compounds to aldehyde under batch/continuous flow module is reported. This catalytic transformation is highly selective for syntheses of various aldehydes and does not require any additional additives such as bases and oxidants. Furthermore, the heterogeneous Fe–zeolite catalyst is recoverable and reusable for more than five cycles and offers gram-scale synthesis without the loss of catalytic efficiency. This heterogeneous catalyst has a maximum TOF of 5.93 h–1.

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      Recent Advances in Photodecarboxylations Involving Phthalimides

      Saira Mumtaz, Mark J. Robertson, Michael Oelgemöller

      • James Cook University, College of Science and Engineering, Townsville, Qld 4811, Australia.

      Owing to their favourable photophysical and electrochemical properties, phthalimides undergo a variety of highly efficient photodecarboxylation reactions. These transformations have been applied to the synthesis of macrocyclic compounds as well as bioactive addition adducts. N-Acetoxyphthalimides are versatile precursors to imidyl and alkyl radicals through photodecarboxylation and have subsequently been used for a variety of coupling reactions. The generally mild reaction conditions make these reactions attractive for green chemical applications. The process protocols were successfully transferred to novel photoreactor devices, among these falling film or continuous flow reactors.

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      C–H functionalisation of aldehydes using light generated, non-stabilised diazo compounds in flow†

      Paul Dingwall a, Andreas Greb a, Lorène N. S. Crespin a, Ricardo Labes a, Biagia Musio a, Jian-Siang Poh a, Patrick Pasau b, David C. Blakemore c, Steven V. Ley *a

      • a Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
      • b UCB Biopharma SPRL, Chemical Research R5, Chemin du Foriest 1420, Braine-L’Alleud, Belgium 
      • c Medicine Design, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, USA

      The difficulty in accessing and safely utilising non-stabilised diazo species has in the past limited the application of this class of compounds. Here we explore further the use of oxadiazolines, non-stabilised diazo precursors which are bench stable, in direct, non-catalytic, aldehyde C–H functionalisation reactions under UV photolysis in flow and free from additives. Commercially available aldehydes are coupled to afford unsymmetrical aryl–alkyl and alkyl–alkyl ketones while mild conditions and lack of transition metal catalysts allow for exceptional functional group tolerance. Examples are given on small scale and in a larger scale continuous production.

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      Catalytic Static Mixers for the Continuous Flow Hydrogenation of a Key Intermediate of Linezolid (Zyvox)

      James Gardiner *, Xuan Nguyen , Charlotte Genet , Mike D. Horne , Christian Hornung , John Tsanaktsidis

      • a CSIRO Manufacturing Flagship, Bayview Avenue, Clayton, Australia
      • b CSIRO Mineral Resources, Bayview Avenue, Clayton, VIC 3169, Australia

      Catalytic static mixers (CSMs) were used for the efficient preparation of a key intermediate of the antimicrobial drug linezolid (Zyvox). The approach combines 3D printing and additive manufacturing techniques with continuous flow processing to produce a general method for catalytic hydrogenations and the rapid production of the target molecule without the need for catalyst removal or recovery.

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      Photoinduced Palladium Negishi Cross-Coupling Through Visible Light Absorption of Palladium-Organozinc complexes

      Irini Abdiaj a, Lena Huck a,b, José Miguel Mateo b, Antonio de la Hoz b, M. Victoria Gomez c, Angel Díaz-Ortiz b, Jesús Alcázar a

      • a Lead Discovery, Janssen Research and Development, Janssen-Cilag, S.A., Jarama 75A, 45007 Toledo, Spain
      • b Facultad de Ciencias y Tecnologías Químicas, Universidad de Castilla-La Mancha, Av. Camilo José Cela 10, 13071 Ciudad Real, Spain
      • c Instituto Regional de Investigación Científica Aplicada, Universidad de Castilla-La Mancha, Av. Camilo José Cela, sn, 13071 Ciudad Real, Spain

      A visible‐light‐induced Negishi cross‐coupling is enabled by the activation of a Pd0–Zn complex. With this photocatalytic method, the scope of deactivated aryl halides that can be employed in the Negishi coupling was significantly expanded. NMR experiments conducted in the presence and absence of light confirmed that the formation of the palladium–zinc complex is key for accelerating the oxidative addition step.

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      Three-Component Assembly of Multiply Substituted Homoallylic Alcohols and Amines Using a Flow Chemistry Photoreactor

      Yiding Chen , David Blakemore , Patrick Pasau §, Steven V. Ley

      • Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
      • Medicine Design, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, United States
      • § UCB Biopharma SPRL, Chemical Research R5, Chemin du Foriest, 1420 Braine-L’Alleud, Belgium

      Oxadiazolines are bench-stable diazo precursors, which are activated under UV radiation in the presence of vinylboronic acids and aldehydes to enable a one-step three-component assembly of densely functionalized homoallylic alcohols. Substitution on all positions of the homoallylic alcohol product were achieved with high functional group tolerance. No catalyst or other additive was required to effect the reaction, which proceeds at 20 °C over 40 min. Imines and indoles were also incorporated, giving access to homoallylic amines.

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      Mild Homologation of Esters via Continuous Flow Chloroacetate Claisen Reactions

      Maximilian A. Ganiek, Maria V. Ivanova, Benjamin Martin* and Paul Knochel*

      • Department of Chemistry, Ludwig-Maximilians-Universität Munich, Butenandtstr. 5 – 13, 81377 Munich, Germany

      The selective chloromethylenation of functionalized esters using chloroacetic acid (CA) and LiHMDS (HMDS = hexamethyldisilazide) in a continuous flow setup is reported. This Claisen homologation is for the first time extended to bis-chloromethylenation using dichloro-acetic acid (DCA), thus giving access to under-explored α,α’-bis-chloroketones. The use of flow conditions enables an efficient generation and reaction of the unstable chloroacetate dianion intermediates, leading to unprecedented mild and scalable reaction conditions at an economic reagent stoichiometry ( 10 °C, < 1 min, 1.0-2.4 equiv. dianion). The clean reaction profiles allows the subsequent use of the unpurified crude products, which is demonstrated in the synthesis of various heterocycles of broad interest. Furthermore, we report a novel, catalyst-free substitution of the obtained monochloro ketone products with (hetero)aryl zinc enolates leading to valuable 1,4-diketones.

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      Regioselective Chlorination of Quinoline Derivatives via Fluorine Mediation in a Microfluidic Reactor

      Hao Qi, Xin Li, Zhuang Liu, Shan‐Shan Miao, Prof. Zheng Fang, Lin Chen, Zheng Fang, Prof. Kai Guo

      • College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, China State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, China

      A novel green and efficient reaction route for the synthesis of 2‐chloroquinoline via N‐fluoride fluorinated by 1‐Chloromethyl‐4‐fluoro‐1,4‐diazoniabicyclo [2.2.2] octane bis(tetrafluoroborate) (Selectfluor) with 1,3‐Dichloro‐5,5‐dimethylhydantoin (DCDMH) in Vapourtec reactor has been developed. In addition, a series of C2 heterocyclic derivative products are obtained in moderate to good yields under no metal conditions.

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      Continuous flow synthesis of a carbon-based molecular cage macrocycle via a three-fold homocoupling reaction

      * Corresponding authors a b Centre for Advanced Nanomaterials and the School of Physical Sciences, The University of Adelaide, Adelaide, Australia Melanie Kitchinab, Kristina Konstasa, Christopher J. Sumbyb, Milena L. Czyza, Peter Valenteb, Matthew R. Hill*ab, Anastasios Polyzos*ac, Christian J. Doonan*ab

      • * Corresponding authors
      • a CSIRO Manufacturing Flagship, Bayview Avenue, Clayton, Australia
      • b Centre for Advanced Nanomaterials and the School of Physical Sciences, The University of Adelaide, Adelaide, Australia

      The facile synthesis of the cage molecule (C110H56Br2) via a remarkable three-fold homo-coupling macrocyclization reaction using continuous flow methodology is reported. Synthesis via continuous flow chemistry improves the residence time, safety, and environmental profile of this synthetically challenging reaction. Further, the new cage possesses halogen atoms at its apex that serve to expand the potential reaction space of these intrinsically porous, all carbon–carbon bonded molecular cage molecules.

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      Flow-based biocatalysis: Application to peracetylated arabinofuranosyl-1,5-arabinofuranose synthesis

      • Teodora Bavaroa
      • Andrea Pintob
      • Federica Dall’Oglioc
      • María J. Hernáizd
      • Carlo F. Morellie
      • Paolo Zambellib
      • Carlo De Michelic
      • Paola Contic
      • Lucia Tamborinic
      • Marco Terrenia
      • a Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy
      • b Department of Food Environmental and Nutritional Science (DeFENS), University of Milan, Via Mangiagalli 25, 20133 Milan, Italy
      • c Department of Pharmaceutical Sciences (DISFARM), University of Milan, Via Mangiagalli 25, 20133 Milan, Italy
      • d Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Complutense University of Madrid, Plaza de Ramón y Cajal s/n, 28040 Madrid, Spain
      • e Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milan, Italy

      The lipase-catalyzed regioselective hydrolysis of peracetylated arabinose was performed in a packed bed flow reactor (PBR). In particular, the hydrolysis of the α  anomer of peracetylated arabinose catalyzed by Novozym® 435 resulted in the monodeprotection of C5 in only 5 min and 91% yield. By using the immobilized Pseudomonas stutzeri lipase, the regioselective hydrolysis of the β  anomer was also accomplished affording the C1 deacetylated derivative in 30 min with good yields. The high local concentration of the immobilized biocatalyst in the PBR allow for a significant reduction of the reaction time; moreover, repeated re-use, and easy downstream processing increase the efficiency and the productivity of the process, if compared to the classical batch procedure. In fact, under optimized conditions, the specific reaction rate of the biocatalyzed flow reaction showed an increase of more than 300 times compared to the batch one. The obtained building blocks were prepared in gram scale and then used for the synthesis of peracetylated arabinofuranosyl-1,5-arabinofuranose.

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      Continuous Flow Photochemical Benzylic Bromination of a Key Intermediate in the Synthesis of a 2‐Oxazolidinone

      A continuous flow protocol for the benzylic photobromination of methyl N,N‐bis(tert‐butoxycarbonyl) phenylalaninate (3) is presented. This photochemical transformation generating brominated intermediate 4 is the critical step in synthesis of oxazolidinone 5, a key intermediate for the preparation of active pharmaceutical ingredients. The reaction was optimized in three continuous flow photoreactors: a self‐made reactor based on a T5 8 W black light lamp, as well as the commercially available VapourTec® UV‐150 and Corning® Advanced‐Flow™ reactors, both equipped with LED light sources. Under optimal conditions, concentrated solutions (95 g/L) of the starting material could be processed on multi‐gram scale, providing high conversion (96%) within 7 min at 30 °C, using 2 equivalents of N‐bromosuccinimide (NBS).

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      Native Chemical Ligation–Photodesulfurization in Flow

      • Timothy S. Chisholm
      • Daniel Clayton
      • Luke J. Dowman
      • Jessica Sayers
      • Richard J. Payne
      • School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia
      Native Chemical Ligation–Photodesulfurization in Flow

      Native chemical ligation (NCL) combined with desulfurization chemistry has revolutionized the way in which large polypeptides and proteins are accessed by chemical synthesis. Herein, we outline the use of flow chemistry for the ligation-based assembly of polypeptides. We also describe the development of a novel photodesulfurization transformation that, when coupled with flow NCL, enables efficient access to native polypeptides on time scales up to 2 orders of magnitude faster than current batch NCL–desulfurization methods. The power of the new ligation–photodesulfurization flow platform is showcased through the rapid synthesis of the 36 residue clinically approved HIV entry inhibitor enfuvirtide and the peptide diagnostic agent somatorelin.

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      Continuous flow biocatalysis

      Joshua Britton, Sudpta Majumdar, Gregory A. Weiss

      • Department of Chemistry, Molecular Biology and Biochemistry, University of California, Irvine, USA

      The continuous flow synthesis of active pharmaceutical ingredients, value-added chemicals, and materials has grown tremendously over the past ten years. This revolution in chemical manufacturing has resulted from innovations in both new methodology and technology. This field, however, has been predominantly focused on synthetic organic chemistry, and the use of biocatalysts in continuous flow systems is only now becoming popular. Although immobilized enzymes and whole cells in batch systems are common, their continuous flow counterparts have grown rapidly over the past two years. With continuous flow systems offering improved mixing, mass transfer, thermal control, pressurized processing, decreased variation, automation, process analytical technology, and in-line purification, the combination of biocatalysis and flow chemistry opens powerful new process windows. This Review explores continuous flow biocatalysts with emphasis on new technology, enzymes, whole cells, co-factor recycling, and immobilization methods for the synthesis of pharmaceuticals, value-added chemicals, and materials.

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      Reductive aminations using a 3D printed supported metal(0) catalyst system

      Charlotte Genet1, Xuan Nguyen1, Bita Bayatsarmadi2, Mike D. Horne2, James Gardiner1, Christian H. Hornung1

      • 1 CSIRO Manufacturing, Clayton, South Australia
      • 2 CSIRO Minerals Resources, Clayton, South Australia

      Additively manufactured catalytic static mixers were used for the intensified reductive amination of aldehydes and ketones inside a continuous flow reactor. This efficient synthesis method is enabled by the use of tubular reactors fitted with 3D printed metal static mixers which are coated with a catalytically active layer, either Pd or Ni. The 3D printing process allows for maximum design flexibility for the mixer scaffold and is compatible with a range of deposition methods including electroplating and metal cold spraying. Single- and multi-stage continuous flow processing yielded high to full conversion and has the potential to scale-up these operations without the need for manual handling of reactive imine intermediates.

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      Flow Synthesis of Coumalic Acid and its Derivatization

      Laura K. Smith and Ian R. Baxendale

      • Department of Chemistry, University of Durham, South Road, Durham, DH1 3LE, UK.

      Coumalic acid is a valuable platform compound which can be prepared from malic acid, a biorenewable feedstock readily derived from the fermentation of glucose. Current batch procedures to synthesise coumalic acid have several drawbacks, which we address with the aid of tubular flow systems and a simple heated rotating flow reactor. The prepared coumalate derivatives can be further used in inverse electron demand Diels-Alder reactions to synthesise compounds with many applications including molecular electronics, with the added advantage of providing metal-free preparations.

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      Combining CH functionalisation and flow photochemical heterocyclic metamorphosis (FP-HM) for the synthesis of benzo [1, 3] oxazepines

      • Jasraj S. Babra, Andrew T. Russell, Christopher D. Smith, Yuxiong Zhang
      • Department of Chemistry, University of Reading, Whiteknights, Reading, RG6 6AD, UK

      C-H Activation/functionalisation and Flow Photochemical Heterocyclic Metamorphosis (FP-HM) have been combined to synthesize a library of benzo [1,3]oxazepines, a rarely described heterocyclic family. This combined protocol allows a range of arylated products to be made from simple starting materials, and the cheap flow photochemical system has proven effective for rapid synthesis of gram-quantities of benzo [1,3]oxazepines.

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      Studies toward the scaling of gas‐liquid photocycloadditions

      Dr. Emily B. Corcoran, Dr. François Lévesque, Dr. Jonathan P. McMullen, Dr. John R. Naber

      • Department of Process Research and Development, Merck Sharp & Dohme Corp., Rahway, USA

      The gas‐liquid biphasic photochemical [2+2] cycloaddition of maleic anhydride with ethylene was identified as a desirable strategy for the divergent synthesis of cyclobutane derivatives. To address the challenge of utilizing this transformation on a larger scale, studies toward the development of a stable process with sufficient productivity were undertaken. These studies revealed the importance of several reaction parameters to enhance both the gas solubility in solution and the efficient utilization of photons from various types of light sources.

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      Photooxygenation in an advanced led-driven flow reactor module: Experimental investigations and modelling

      • Robbie Radjagobalouab
      • Jean-François Blancoa
      • Odile Dechy-Cabaretb
      • Michael Oelgemöllerc
      • Karine Loubièrea
      • a Laboratoire de Génie Chimique LGC, Université de Toulouse, CNRS, Toulouse, France
      • b Laboratoire de Chimie de Coordination LCC, CNRS, Toulouse, France
      • c James Cook University, College of Science and Engineering, Townsville, Queensland 4811, Australia

      The photooxygenation of  α-terpinene was investigated as a benchmark reaction in an advanced LED-driven flow reactor module, both from an experimental and modelling point of view. Ethanol was used as a green solvent and rose Bengal was chosen as a cheap sensitizer of industrial importance. Firstly, the kinetic law based on all mechanistic steps was established for the chosen photooxygenation. From this, the set of operating parameters potentially influencing the photoreaction rate were identified. Subsequently, experiments were carried out under continuous-flow conditions to screen these operating parameters, namely concentration of α-terpinene, concentration of photosensitizer, residence time, structure of the segmented gas-liquid flow and nature of the reagent gas phase (air versus pure oxygen). Finally, the conditions enabling minimization of sensitizer bleaching were established. It was also shown that the hydrodynamic characteristics of the gas-liquid flow can have an effect on the conversion levels. From this, a simplified model was proposed to predict the conversion at the reactor’s outlet when pure oxygen was used.

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      P‐121: Successive and scalable synthesis of highly stable Cs4PbBr6 perovskite microcrystal by microfluidic system and their application in backlight display

      Hung-Chia Wang1, Zhen Bao1, Ru-Shi Liu1,2

      • 1 Department of Chemistry, National Taiwan University, Taipei, Taiwan
      • 2 Department of Mechanical Engineering and Graduate Institute of Manufacturing Technology, National Taipei University of Technology, Taipei, Taiwan

      All Inorganic CsPbX3 (X = I, Br, Cl) perovskite nanocrystal have attracted immense research interest in recent years, due to their high photoluminescence quantum yield (PLQY). These fascinating features of inorganic nanocrystals have been utilized in light emitting diodes (LEDs) device. However, maintaining the high PLQY in the solid state remains a big challenge. Inorganic mesoporous silica encapsulation of NCs has moderate improvements, but it remains an unsolved problem. Robust and air‐stable Cs4PbBr6microcrystal was another choice in perovskite solid. In this study, we report mass production of Cs4PbBr6 perovskite microcrystal by microfluidic system. To demonstrate the potential application of Cs 4PbBr6 perovskite microcrystal, we fabricated white‐light LEDs based on Cs4PbBr6 and K2SiF6:Mn4+ phosphor. Our white light LED device for backlight display having the NTSC value is 115%.

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      Self-sustaining closed-loop multienzyme-mediated conversion of amines into alcohols in continuous reactions

      Martina L. Contente, Francesca Paradisi

      • School of Chemistry, University of Nottingham, Nottingham, United Kingdom

      The synthesis of alcohols from amine starting materials is an excellent yet challenging strategy for the preparation of pharmaceuticals and polymers. Here we developed a versatile, self-sustaining closed-loop multienzymatic platform for the biocatalytic synthesis of a large range of non-commercially available products in a continuous flow with excellent yields (80 to >99%), reaction times and optical purity of secondary alcohols (>99 enantiomeric excess). This process was also extended to the conversion of biogenic amines into high-value alcohols, such as the powerful antioxidant hydroxytyrosol, and the synthesis of enantiopure 2-arylpropanols via the dynamic kinetic resolution of commercially affordable racemic amines. The system exploits the in situ immobilization of transaminases and redox enzymes which were combined to cater for a fully automated, ultra-efficient synthetic platform with cofactor recycling, in-line recovery of benign by-products and recirculation of the aqueous media that contains the recycled cofactors in catalytic amounts, which increases the efficiency of the system by over 20-fold.

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      Dichlorophenylacrylonitriles as AhR Ligands displaying selective breast cancer cytotoxicity in vitro

      Jennifer R Baker1, Jayne Gilbert2, Stefan Paula3, Xiao Zhu3, Jennette A Sakoff2, Adam McCluskey1

      • 1 The University of Newcastle, Chemistry, Newcastle, Australia
      • 2 Calvary Mater Hospital, Medical Oncology, Newcastle, Australia
      • 3 Purdue University, Chemistry, West Lafayette, United States

      Knoevenagel condensation of 3,4‐dichloro‐ and 2,6‐dichloro‐ phenylacetonitriles gave a library of dichlorophenylacrylonitriles. Our leads 5 and 6 displayed 0.56±0.03 and 0.127±0.04 μM growth inhibition (GI₅₀) and 260‐fold selectivity for the MCF‐7 breast cancer cell line. A 2,6‐dichlorophenyl moiety saw a 10‐fold potency loss; additional nitrogen moieties (‐NO₂) enhanced activity (26 and 27), with the corresponding ‐NH₂ analogues (29 and 30) more potent. Despite this, both 29 (2.8±0.03 μM) and 30 (2.8±0.03 μM) were 10‐fold less cytotoxic than 6. A bromine moiety effected a 3‐fold enhancement in solubility with 18 relative to 5 at 211 μg mL‐1. Modelling led synthesis saw the introduction of 4‐aminophenyl substituent gave 35 and 38, 0.030±0.014 and 0.034±0.01 μM potent, respectively. Other analogues, e.g. 35 and 36, were sub‐micromolar potent against our cell line panel (HT29, colon; U87 and SJ‐G2, glioblastoma; A2780, ovarian; H460, lung; A431, skin; Du145, prostate; BE2‐C neuroblastoma; MIA, pancreas and SMA murine glioblastoma) except 35 against U87. A more extensive evaluation of 38 ((Z)‐N‐(4‐(2‐cyano‐2‐(3,4‐dichlorophenyl)vinyl)phenyl)acetamide), in a panel of drug resistant breast carcinoma cell lines showed 10‐206 nM potency against MDAMB468, T47D, ZR‐75‐1, SKBR3 and BT474. MOE docking scores showed a good correlation between predicted binding efficiencies and observed MCF‐7 cytotoxicity. This supports the use of this model in developing breast cancer specific drugs.

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      Combining C-H functionalisation and flow photochemical heterocyclic metamorphosis (FP-HM) for the synthesis of benzo[1,3]oxazepines

      • Jasraj S. Babra, Andrew T. Russell, Christopher D. Smith, Yuxiong Zhang
      • Department of Chemistry, University of Reading, Whiteknights, Reading, RG6 6AD, UK

      C-H Activation/functionalisation and Flow Photochemical Heterocyclic Metamorphosis (FP-HM) have been combined to synthesize a library of benzo [1,3]oxazepines, a rarely described heterocyclic family. This combined protocol allows a range of arylated products to be made from simple starting materials, and the cheap flow photochemical system has proven effective for rapid synthesis of gram-quantities of benzo [1,3]oxazepines.

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      Multistep Continuous-Flow Processes for the Preparation of Heterocyclic Active Pharmaceutical Ingredients

      Romaric Gérardy, Jean-Christophe M. Monbaliu

      • Center for Integrated Technology and Organic Synthesis, Department of Chemistry, University of Liège, Liège, Belgium

      Flow chemistry has many fascinating facets, among which the most challenging is arguably the implementation of complex multistep processes within one uninterrupted fluidic network. This document provides a thorough overview of some of the most representative examples of multistep continuous-flow strategies in the specific context of preparing heterocyclic active pharmaceuticals. Selected examples emphasizing the implementation of multistep sequences, including various combinations of chemical transformations, purifications, or in-line analysis, are discussed.

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      Flow Chemistry Approaches Applied to the Synthesis of Saturated Heterocycles

      Marcus Baumann, Ian R. Baxendale

      • Department of Chemistry, University of Durham, Durham, UK

      Continuous-flow processing approaches are having a significant impact on the way we devise and perform chemical synthesis. Flow chemistry has repeatedly demonstrated numerous improvements with respect to synthesis efficiency, process safety and ease of reaction scale-up. In recent years flow chemistry has been applied with remarkable success to the generation of valuable target structures across a range of industries from basic bulk chemical manufacture and materials development to flavours, food and cosmetic applications. However, due to its earlier implementation, it has found so far many more advocates in areas of medicinal and agrochemical research and manufacture. In this review article, we summarise the key developments that continuous-flow synthesis has had in the area of saturated heterocycles, specifically focusing on approaches that generate these important entities from acyclic precursors.

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      An efficient benzoxaborole one‐pot synthesis by SiliaCat DPP‐Pd heterogeneous catalysis using diboronic acid

      Kana kunihiro1, Laurence Dumais2, Guillaume Lafitte2, Emeric Varvier2, Loïc Tomas2, Craig Harris2

      • 1 Ecole Nationale Supérieure des Ingenieurs en Arts Chimiques et Technologiques, France
      • 2 Nestlé Skin Health, Galderma R&D, France

      Organoboron compounds are valuable molecules of increasing interest in organic synthesis, catalysis, biology and medicine. Among them, benzoxaboroles emerged as promising building blocks for numerous research programs. In this letter, we communicate the development of new conditions for the one‐pot benzoxaborole synthesis by SiliaCat DPP‐Pd catalysis using diboronic acid as the boron source. This low cost and sustainable strategy permitted the preparation of a useful range of benzoxaborole building blocks. Finally, the transformation was extended to a continuous flow process using our Vapourtec system.

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      Total Synthesis of Neomarchantin A: Key Bond Constructions Performed Using Continuous Flow Methods

      • Émilie Morin, Michaël Raymond, Amaury Dubart, and Shawn K. Collins
      • Department of Chemistry and Centre for Green Chemistry and Catalysis, Université de Montréal, CP 6128 Station Downtown, Montréal, Québec, Canada H3C 3J7

      A synthesis of neomarchantin A has been achieved wherein key bond constructions involving C–O or C–C bond formations were augmented via continuous flow techniques. Of note, the synthesis of neomarchantin A represents the first demonstration of catalytic macrocyclic olefin metathesis as a key step for the synthesis of a macrocyclic bisbibenzyl natural product.

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      In situ epoxide generation by dimethyldioxirane oxidation and the use of epichlorohydrin in the flow synthesis of a library of β-amino alcohols

      Peter J. Cossar, Jennifer R. Baker, Nicholas Cain, Adam McCluskey

      • Chemistry, The University of Newcastle, University Drive Callaghan, New South Wales 2308, Australia

      The flow coupling of epichlorohydrin with substituted phenols, while efficient, limits the nature of the epoxide available for the development of focused libraries of β-amino alcohols. This limitation was encountered in the production of analogues of 1-(4-nitrophenoxy)-3-((2-((4-(trifluoromethyl)pyrimidin-2-yl)amino)ethyl)amino)propan-2-ol 1, a potential antibiotic lead. The in situ (flow) generation of dimethyldoxirane (DMDO) and subsequent flow olefin epoxidation abrogates this limitation and afforded facile access to structurally diverse β-amino alcohols. Analogues of 1 were readily accessed either via (i) a flow/microwave hybrid approach, or (ii) a sequential flow approach. Key steps were the in situ generation of DMDO, with olefin epoxidation in typically good yields and a flow-mediated ring opening aminolysis to form an expanded library of β-amino alcohols 1 and 10a–18g, resulting in modest (11a, 21%) to excellent (12g, 80%) yields. Alternatively flow coupling of epichlorohydrin with phenols 4a–4m (22%–89%) and a Bi(OTf)3catalysed microwave ring opening with amines afforded a select range of β-amino alcohols, but with lower levels of aminolysis regiocontrol than the sequential flow approach.

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      Safe Use of Hazardous Chemicals in Flow

      MT Rahman1, T Wirth2

      • 1 School of Chemistry and Chemical Engineering, Queen’s University Belfast, Belfast, UK
      • 2 School of Chemistry, Cardiff University, Cardiff, UK

      Flow chemistry has evolved into an excellent toolkit for handling challenging chemical transformations during the past decade. Highly exothermic and kinetically fast reactions are difficult to handle even on a small scale, whereas any scale-up poses significant risks when conventional reactors are considered. Flow chemistry enables exquisite control over mixing sequences, reaction time and quenching that ultimately paves the way for the fine-tuning of chemical reactivity in ‘space and time’. This chapter describes recent advances of flow chemistry in controlling and even discovering new reactivities of highly hazardous chemical species and unstable intermediates. This chapter compiles intriguing recent examples manifesting the power of flow chemistry to perform commonly known‚ cryogenic reactions at or near room temperature, safe-handling and in situ production of hazardous or toxic reagents for chemical transformations that are generally considered unsafe in conventional reactors.

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      Photochemical Synthesis of Heterocycles: Merging Flow Processing and Metal-Catalyzed Visible Light Photoredox Transformati

      T Glasnov

      • Institute of Chemistry, University of Graz, Graz, Austria

      The ubiquitous presence of heterocyclic moieties in everyday life justifies the ongoing intensive research within the synthetic community to discover effective methodologies for their construction. As the social concern regarding environmental protection gains importance, the use of light as the ultimate green promoter for chemical reactions has been revived in the scientific community. Specifically, visible-light photoredox processes based on metal- and organic photosensitizer are attracting significant attention and have seen an exceptional advance recently.

      Additionally, continuous-flow processing has enabled a safer and more efficient generation of various heterocycles, whilst allowing their syntheses in a scalable manner. In this chapter, recent achievements in the area of continuous-flow aided photoredox synthesis are covered, including some general remarks on instrumentation, theoretical background and selected flow UV-photochemistry examples.

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      Flow Chemistry as a Drug Discovery Tool: A Medicinal Chemistry Perspective

      Andrew R. Bogdan1, Michael G. Organ2

      • 1 Discovery Chemistry and Technology, AbbVie Inc., North Chicago, USA
      • 2 Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Canada

      The applications of flow chemistry in a drug discovery environment are discussed within. The development of integrated synthesis–bioassay platforms is discussed in the context of enabling medicinal chemistry programs, as is the use of flow chemistry to facilitate intermediate scale-up in a lead optimization setting. Emerging chemical technologies are also discussed, highlighting the use of high temperatures, hazardous gases, and photochemistry in flow to support medicinal chemistry efforts.

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      Copper mediated, heterogeneous, enantioselective intramolecular Buchner reactions of α-diazoketones using continuous flow processing

      • DC Crowley
      • D Lynch
      • AR Maguire
      • School of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Cork T12 K8AF, Ireland
      • School of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Cork T12 K8AF, Ireland

      Enantioselective intramolecular Buchner reactions of α-diazoketones can be effected using heterogeneous copper–bis(oxazoline) catalysts in batch or using continuous flow processing in up to 83% ee. The catalyst can be reused up to 7 times without loss of activity. For α-diazoketones 3 and 4, the enantioselection achieved in flow with the immobilized catalyst was comparable with the standard homogeneous catalyzed process.

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      Functionalization of Heteroarenes Under Continuous Flow

      Joachim Demaerel, Vidmantas Bieliũnas, Wim M. De Borggraeve

      • Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Leuven, Belgium

      Aromatic heterocycles are omnipresent motifs in pharmaceutical and agrochemical structures. Functionalization of these ring systems is an important part of many synthetic procedures. In this chapter, an overview is given of how microflow technology has been employed as a powerful tool for the diversification of heteroarenes. An emphasis is put on fine chemical synthesis, although reactor design and problem solving will be discussed when relevant, as it comprises an important part of the research field. Pragmatic translations to microflow are reviewed for existing functionalization protocols, and a few elusive reactions are highlighted that cannot be performed satisfyingly in batch mode.

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      Photoredox Iridium–Nickel Dual-Catalyzed Decarboxylative Arylation Cross-Coupling: From Batch to Continuous Flow via Self-Optimizing Segmented Flow Reactor

      • Hsiao-Wu Hsieh
      • Connor W. Coley
      • Lorenz M. Baumgartner
      • Klavs F. Jensen*‡
      • Richard I. Robinson*†
      • Global Discovery Chemistry − Chemical Technology Group, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
      • Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States

      Photoredox decarboxylative cross-coupling via iridium–nickel dual catalysis has emerged as a valuable method for C(sp2)–C(sp3) bond formation. Herein we describe the application of a segmented flow (“microslug”) reactor equipped with a newly designed photochemistry module for material-efficient reaction screening and optimization. Through the deployment of a self-optimizing algorithm, optimal flow conditions for the model reaction were rapidly developed, simultaneously accounting for the effects of continuous variables (temperature and time) and discrete variables (base and catalyst). Temperature was found to be a critical parameter with regard to reaction rates and hence productivity in subsequent scale-up in flow. The optimized conditions identified at microscale were found to directly transfer to a Vapourtec UV-150 continuous flow photoreactor, enabling predictable scale-up operation at a scale of hundreds of milligrams per hour. This optimization approach was then expanded to other halide coupling partners that were low-yielding in batch reactions, highlighting the practical application of this optimization platform in the development of conditions for photochemical synthesis in continuous flow.

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      A combination of flow and batch mode processes for the efficient preparation of mGlu2/3 receptor negative allosteric modulators (NAMs)

      • Raveendra Panickar Dhanya, Ananda Herath, Douglas J. Sheffler, Nicholas D.P. Cosford
      • Cancer Metabolism and Signaling Networks Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA

      Benzodiazepinones are privileged scaffolds with activity against multiple therapeutically relevant biological targets. In support of our ongoing studies around allosteric modulators of metabotropic glutamate receptors (mGlus) we required the multigram synthesis of a β-ketoester key intermediate. We report the continuous flow synthesis of tert-butyl 3-(2-cyanopyridin-4-yl)-3-oxopropanoate and its transformation to potent mGlu2/3 negative allosteric modulators (NAMs) in batch mode.

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      On-demand synthesis of organozinc halides under continuous flow conditions

      Mateo Berton, Lena Huck, Jesús Alcázar

      • Lead Discovery, Janssen Research and Development, Janssen-Cilag, S.A., Toledo, Spain

      Organozinc reagents are versatile building blocks for introducing C(sp2)-C(sp3) and C(sp3)-C(sp3) bonds into organic structures. However, despite their ample synthetic versatility and broad functional group tolerance, the use of organozinc reagents in the laboratory is limited because of their instability, exothermicity and water sensitivity, as well as their labor-intensive preparation. Herein, we describe an on-demand synthesis of these useful reagents under continuous flow conditions, overcoming these primary limitations and supporting widespread adoption of these reagents in synthetic organic chemistry. To exemplify this procedure, a solution of ethyl zincbromoacetate is prepared by flowing ethyl bromoacetate through a column containing metallic zinc. The temperature of the column is controlled by a heating jacket and a thermocouple in close contact with it. Advice on how to perform the procedure using alternative equipment is also given to allow a wider access to the methodology. Here we describe the preparation of 50 ml of solution, which takes 1 h 40 min, although up to 250–300 ml can be prepared with the same column setup at a rate of 30 ml per h. The procedure provides the reagent as a clean solution with reproducible concentration. Organozinc solutions generated in flow can be coupled to a second flow reactor to perform a Reformatsky reaction or can be collected over a flask containing the required reagents for a batch Negishi reaction.

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      Generation of Diversity Sets with High sp3 Fraction Using the Photoredox Coupling of Organotrifluoroborates and Organosilicates with Heteroaryl/Aryl Bromides in Continuous Flow

      • Kevin D Raynor, Gregory D May, Upul K. Bandarage, and Michael J. Boyd
      • Vertex Pharmaceuticals Inc., 50 Nothern Avenue, Boston, Massachusetts 02210, United States

      The photoredox cross-coupling of aryl halides and potassium alkyl trifluoroborates is a very effective means to form Csp3-Csp2 bonds. However, this transformation is inefficient for the coupling of unactivated primary trifluoroborates. We have developed a generally useful, continuous flow Csp3-Csp2 coupling procedure for the synthesis of diverse product sets that is compatible with both trifluoroborates and silicate reagents. This universal protocol provides diversity sets from both primary and secondary coupling partners. This easily scalable procedure widens the substrate scope of the coupling reaction and is efficient for producing a greater range of analogues bearing a high sp3 fraction.

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      Iron-Catalyzed Batch/Continuous Flow C-H Functionalization Module for the Synthesis of Anticancer Peroxides

      • Moreshwar Bhagwan Chaudhari, Suresh Moorthy, Sohan Patil, Girish Singh Bisht, Haneef Mohamed, Sudipta Basu, and Boopathy Gnanaprakasam
      • Department of Chemistry, Indian Institute of Science Education and Research, Pune 411008, India

      Iron-catalyzed dehydrogenative cross-coupling of carbonyl compounds with aliphatic peroxide was developed under mild conditions. A library of linear alkylated and arylated peroxides are synthesized in good to excellent yield. This method is highly selective and general for a range of biologically important derivatives of 2-oxindole, barbituric acid, and 4-hydroxy coumarin with a good functional group tolerance and without the cleavage of the peroxide bond. This peroxidation reaction is upscalable to grams and also synthesizable in continuous flow with increased safety in short duration. Mechanistic investigation reveals Fe-(II) undergoes redox type process to generate the radical intermediates, which subsequently recombine selectively to form the stable peroxides. The potential of peroxides is evaluated by cell viability assay and found to exhibit the good anticancer activity with minimum IC50= 5.3 μM.

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      Selective N-monomethylation of primary anilines with dimethyl carbonate in continuous flow

      Hyowon Seo, Anne-Catherine Bédard, Willie P. Chen, Robert W. Hicklin, Alexander Alabugin, Timothy F. Jamison

      • Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139, USA

      Selective N-monomethylation of anilines has been achieved under continuous flow conditions using dimethyl carbonate as a green methylating agent in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene. Our methodology takes advantage of the expanded process windows available in the continuous flow regime to safely induce monomethylation in superheated solvents at high pressure. We propose selective N-monomethylation is achieved via an in situ protection-deprotection pathway, which is supported by the observed reactivities of several putative reaction intermediates. The robust and scalable method was applicable to a broad range of primary aniline substrates including ortho-, meta-, and para-substituted anilines, as well as electron-rich and electron-deficient anilines. The synthetic precursor of diazepam, 5-chloro-2-(methylamino)benzophenone, was selectively synthesized under our optimized conditions.

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      Continuous flow multistep synthesis of α-functionalized esters via lithium enolate intermediates

      Timo von Keutza,b, Franz J. Straussb, David Cantilloa,b, C. Oliver Kappea,b

      • a Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
      • b Institute of Chemistry, NAWI Graz, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria

      This manuscript describes a continuous flow protocol for the α-alkylation of esters. The method is based on the generation of lithium enolate intermediates from the esters and in situ delivered LDA. The process is then integrated with the electrophilic addition step and a quench in line. A series of α-functionalized ester have been prepared using this procedure with moderate to good yields. Key reaction parameters such as temperature and residence time and their influence on the reaction outcome are discussed in detail.

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

      Marcus Baumann, Ian R. Baxendale and Fabien Deplante

      • Department of Chemistry, University of Durham, South Road, Durham, Durham, DH1 3LE, UK

      An assembled suite of flow-based transformations have been used to rapidly scale-up the production of a novel auxin mimic-based herbicide which was required for preliminary field trials. The overall synthetic approach and optimisation studies are described along with a full description of the final reactor configurations employed for the synthesis as well as the downstream processing of the reaction streams.

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      Synthesis, physicochemical properties, and biological activity of bile acids 3-glucuronides: Novel insights into bile acid signalling and detoxification

      Serena Mostardaa, Daniela Passerib, Andrea Carottia,1, Bruno Cerraa, Carolina Collivab, Tiziana Benicchib, Antonio Macchiaruloa, Roberto Pellicciarib, Antimo Gioielloa

      • a Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo, 1, 06123 Perugia, Italy
      • b TES Pharma, Corso Vannucci, 47, 06121 Perugia, Italy

      Glucuronidation is considered an important detoxification pathway of bile acids especially in cholestatic conditions. Glucuronides are less toxic than the parent free forms and are more easily excreted in urine. However, the pathophysiological significance of bile acid glucuronidation is still controversial and debated among the scientific community. Progress in this field has been strongly limited by the lack of appropriate methods for the preparation of pure glucuronides in the amount needed for biological and pharmacological studies. In this work, we have developed a new synthesis of bile acid C3-glucuronides enabling the convenient preparation of gram-scale quantities. The synthesized compounds have been characterized in terms of physicochemical properties and abilities to modulate key nuclear receptors including the farnesoid X receptor (FXR). In particular, we found that C3-glucuronides of chenodeoxycholic acid and lithocholic acid, respectively the most abundant and potentially cytotoxic species formed in patients affected by cholestasis, behave as FXR agonists and positively regulate the gene expression of transporter proteins, the function of which is critical in human conditions related to imbalances of bile acid homeostasis.

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      Conjugated polymers via direct arylation polymerization in continuous flow: minimizing the cost and batch-to-batch variations for high-throughput energy conversion

      Nemal S. Gobalasingham1, Jon E. Carlé2, Frederik C. Krebs2, Barry C. Thompson1, Eva Bundgaard2, Martin Helgesen*,2

      • 1 Department of Chemistry and Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, California, 90089-1661
      • 2 DTU Energy, Technical University of Denmark, Roskilde, DK-4000, Denmark

      Continuous flow methods are utilized in conjunction with direct arylation polymerization (DArP) for the scaled synthesis of the roll-to-roll compatible polymer, poly[(2,5-bis(2-hexyldecyloxy)phenylene)-alt-(4,7-di(thiophen-2-yl)-benzo[c][1,2,5]thiadiazole)] (PPDTBT). PPDTBT is based on simple, inexpensive, and scalable monomers using thienyl-flanked benzothiadiazole as the acceptor, which is the first β-unprotected substrate to be used in continuous flow via DArP, enabling critical evaluation of the suitability of this emerging synthetic method for minimizing defects and for the scaled synthesis of high-performance materials. To demonstrate the usefulness of the method, DArP-prepared PPDTBT via continuous flow synthesis is employed for the preparation of indium tin oxide (ITO)-free and flexible roll-coated solar cells to achieve a power conversion efficiency of 3.5% for 1 cm2 devices, which is comparable to the performance of PPDTBT polymerized through Stille cross coupling. These efforts demonstrate the distinct advantages of the continuous flow protocol with DArP avoiding use of toxic tin chemicals, reducing the associated costs of polymer upscaling, and minimizing batch-to-batch variations for high-quality material.

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      Recent advances of microfluidics technologies in the field of medicinal chemistry

      László Ürge*, Jesus Alcazar, Lena Huck, György Dormán

      • * DBH Group, Budapest, Hungary
      • Janssen Research and Development, Toledo, Spain
      • Innostudio Inc., Budapest, Hungary

      Microfluidics, mesofluidics, and lab-on-a-chip technologies have been extensively researched in the pharma and life science industry over the last two decades, including synthesis of novel compounds and building blocks, medicinal chemistry support, biological screening, DMPK studies, and formulation and manufacturing of APIs and final products. These technologies can provide significant advantages over traditional methods and have the potential to revolutionize certain aspects of pharma R&D. The recent developments on the application of these novel techniques, their penetration in the industry, and their barriers for the further adaptation will be extensively discussed in this overview.

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      Sustainable flow synthesis of a versatile cyclopentenone building block

      Marcus Baumann, Ian R. Baxendale, Paolo Filipponi, Te Hu

      • Department of Chemistry, University of Durham, South Road, DH1 3LE Durham, U.K
      • Novartis Pharma AG, Fabrikstrasse 14, 4002 Basel, Switzerland

      A flow based multistep processing sequence to reliably provide the delivery of a highly functional cyclopentenone is described. The exemplification of employing solid dosing of reagents and in-line aqueous extraction has enabled an integrated workflow in a highly automated reactor setup.

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      Auto-Tandem Catalysis: Pd(II)-Catalysed Dehydrogenation/Oxidative Heck of Cyclopentane-1,3-diones

      Claire J C Lamb, Bryan G Nderitu, Gemma McMurdo, John MTobin, Filipe Vilela, and Ai-Lan Lee

      • Institute of Chemical Sciences, Heriot-Watt University, Edinburgh EH14 4AS, United Kingdom

      A Pd(II) catalyst system has been used to successfully catalyse two mechanistically distinct reactions in a one-pot procedure: dehydrogenation of 2,2-disubstituted cyclopentane-1,3-diones and
      the subsequent oxidative Heck coupling. This auto-tandem catalytic reaction is applicable to both batch and continuous flow processes, with the latter being the first example of a tandem aerobic dehydrogenation/oxidative Heck in flow. In addition, a telescoped reaction involving enantioselective desymmetrisation of the all-C quaternary centre was successfully achieved.

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      Exploring effects of intermittent light upon visible light promoted water oxidations

      Dominic Walsh*a, Pascaline Patureaua, Karen Robertsona, Shaun Reekstingb, Anneke Lubbenb, Salvador Eslavac, Mark T. Welleraa

      • a Department of Chemistry, University of Bath, Bath, BA2 7AY, UK. E-mail: d.walsh2@bath.ac.uk
      • b Chemical Characterization and Analysis Facility, University of Bath, Bath, BA2 7AY, UK
      • c Department of Chemical Engineering, University of Bath, BA2 7AY, UK

      Visible light promoted photocatalytic water oxidations for potential solar fuel production have been studied widely, with many reports on optimization of reagent components. Here we report an exploration on the effects upon ongoing reactions of daylight equivalent light intensity illumination with regulated short dark periods of a few seconds duration as compared to standard continuous illumination. Comparison was made with systems employing synthesized low cost earth abundant iron oxide, calciumoxomanganite and cobalt oxide nanoparticulate catalysts together with a [Ru(bpy)3] 2+ light harvesting dye and an electron acceptor. Yields of gaseous O2 and proton production were measured in situ and in real time. The study found that low cost catalysts could give very significantly increased O2 yields, turn over frequency and improved reaction profiles by use of simple on/off illumination. A range of timings with identical overall photon flux were tested and an optimum determined. Analysis of effects upon the light sensitizer under the range of lighting conditions (through mass spectrometry and UV-vis measurements), together with implementation of a continuous flow system as comparison to the batch reactions, were all employed to help elucidate the mechanisms for the clear improvements in reaction yields observed. These are believed to stem from reduction in self-decomposition of excess oxidized sensitizer and better synchronization of cyclic sensitizer oxidation/reductions with water oxidation at the
      metal oxide surface at specific light on : off timing.

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      Telescoped continuous flow generation of a library of highly substituted 3-thio-1,2,4-triazoles.

      Mariana C. F. C. B. Damiãoa, Renan Galavernaa, Alan P. Kozikowskib, James Eubanksc, Julio C. Pastrea

      • a Institute of Chemistry, University of Campinas - UNICAMP, PO Box 6154 - Zip Code 13083-970, Campinas, SP, Brazil
      • b StarWise Therapeutics LLC - University Research Park – Zip Code 53719-1235, Madison, Wisconsin, USA
      • c Division of Genetics and Development - Krembil Research Institute – Zip Code M5T 2S8, Toronto, Ontario, Canada

      We report herein the successful application of continuous flow micro reactors to prepare important building blocks based on the 3-thio-1,2,4-triazole core. A telescoped continuous flow process was developed based on the condensation of hydrazides and isothiocyanates to deliver an in situ stream of a thiosemicarbazide, which subsequently was cyclized under basic conditions. The obtained 1,2,4-triazole-3-thiol was further alkylated with benzyl/alkyl halides. In addition, we evaluated the scope of heterocycle formation and alkylation using different hydrazides, isothiocyanates, and aryl/alkyl chlorides, bromides and iodides. We were able to synthesize a small library of 18 compounds in 48 minutes of residence time for each synthesis, and in moderate to excellent yields, in a telescoped fashion. The fully integrated synthesis flow platform enables the fast generation of compound libraries, reducing the time consumed in preliminary stages of a drug discovery process.

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      Targeting a mirabegron precursor by BH3-mediated continuous flow reduction process

      Sonia De Angelisa, Claudia Carluccia, Modesto de Candiaa, Gabriele Rebuzzinib, Paolo Celestinib, Massimiliano Riscazzib, Renzo Luisia, Leonardo Degennaroa

      • a FLAME-Lab − Flow Chemistry and Microreactor Technology Laboratory, Department of Pharmacy — Drug Sciences, University of Bari “A. Moro” Via E. Orabona 4, Bari 70125, Italy
      • b COSMA S.p.A, Via Colleoni 15/17, Ciserano, BG 24040, Italy

      A continuous-flow reduction of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide, involved in the synthetic pathway of Mirabegron, has been developed. This study demonstrated the possibility to safely handling BH3 complexes within microfluidic reactors using 2-MeTHF as greener alternative to traditional solvents, and without requiring any additive such as DMI. In addition, NMR and HPLC purity analysis revealed that the sole by-product of this process is the diamine 3, which wouldn’t affect the following synthetic steps towards Mirabegron.

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      In Situ Preparation and Consumption of O-Mesitylsulfonylhydroxylamine (MSH) in Continuous Flow for the Amination of Pyridines

      Cara E. Brocklehurst*, Guido Koch, Stephanie Rothe-Pöllet, Luigi La Vecchia

      • Synthesis and Technologies, Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Klybeckstrasse 141, 4057 Basel, Switzerland

      The paper demonstrates a safe method in which highly unstable O-mesitylsulfonylhydroxylamine (MSH) can be prepared and consumed in continuous flow. MSH was prepared in situ and used for the flow amination of a range of pyridines, which were subsequently transformed into useful pyrazolopyridine building blocks.

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      Highly efficient oxidation of amines to aldehydes with flow-based biocatalysis

      Dr. Martina L. Contente1,2, Federica Dall'Oglio3, Dr. Lucia Tamborini3, Prof. Francesco Molinari4, Prof. Francesca Paradisi1,2

      • 1 School of Chemistry, University of Nottingham, Nottingham, UK
      • 2 UCD School of Chemistry, University College Dublin, Dublin, Ireland
      • 3 Department of Pharmaceutical Sciences, DISFARM, University of Milan, Milan, Italy
      • 4 Department of Food, Environmental and Nutritional Science, DeFENS, University of Milan, Milan, Italy

      A new mild and efficient process for the aqueous preparation of aldehydes, which are employed as flavour and fragrance components in food, beverage, cosmetics, as well as in pharmaceuticals, was developed using a continuous-flow approach based on an immobilised pure transaminase-packed bed reactor. HEWT, an ω-transaminase from the haloadapted bacterium Halomonas elongata, has been selected for its excellent stability and substrate scope. Sixteen different amines were rapidly (3–15 min) oxidised to the corresponding aldehydes (90 to 99 %) with only 1 to 5 equivalents of sodium pyruvate. The process was fully automated, allowing for the in-line recovery of the pure aldehydes (chemical purity >99 % and isolated yields above 80 %), without any further work-up procedure.

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      Novel Polystyrene-Immobilized Chiral Amino Alcohols as Heterogeneous Ligands for the Enantioselective Arylation of Aldehydes in Batch and Continuous Flow Regime

      José AugustoForni, Luiz Fernando Toneto, Novaes, Renan Galaverna, Julio C.Pastre

      • Institute of Chemistry, University of Campinas – UNICAMP, PO Box 6154, 13083-970, Campinas, SP, Brazil

      Six different ligands derived from (S)-proline, (2S,4R)-4-hydroxyproline, (S)-tyrosine and (S)-phenylalanine were synthesized and screened in homogeneous phase for the enantioselective arylation of aldehydes using mixed organozinc reagents. The best ligands were immobilized on the Merrifield resin and evaluated in batch and continuous flow regimes. In batch, up to 89% yield and 90:10 enantiomeric ratio were obtained. In continuous flow regime, we explored the examples that were more challenging in batch, being able to obtain the desired product in 88% yield and 94:6 of enantiomeric excess in residence time as low as 1.5 min.

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      An efficient and green pathway for continuous Friedel-Crafts acylation over α-Fe2O3 and CaCO3 nanoparticles prepared in the microreactors

      Zheng Fanga1, Wei Heb1, Tao Tub, Niuniu Lva, Chuanhong Qiua, Xin Lia, Ning Zhua, Li Wana, Kai Guoac

      • a College of Biotechnology and Pharmaceutical Engineering, Nanjing Technology University, No. 30 Puzhu South Road, Nanjing, 211816, PR China
      • b Department of Chemistry, Fudan University, No. 220 Handan Road, Shanghai, 200433, PR China
      • c State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Technology University, No. 30 Puzhu South Road, Nanjing, 211816, PR China

      α-Fe2O3 nanoparticles were prepared by using a continuous precipitation method with a valve assisted micromixer in the presence of iron (III) sulfate and ammonia water. The resulting nanoparticles were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM). Meanwhile, CaCO3 nanoparticles were synthesized in a tube-in-tube flow reactor AF-2400. The acylation process catalyzed by modified lipophilic α-Fe2O3 and CaCO3 nanoparticles in the flow reactor were systematically investigated. Under the optimal conditions, a yield of 97.8% was obtained. Addition of CaCO3 nanoparticles resulted in higher catalytic efficiency compared with pure modified α-Fe2O3 nanoparticles. Moreover, this novel acylation also worked well for other substrates.

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      A nanoporous graphene analog for superfast heavy metal removal and continuous-flow visible-light photoredox catalysis

      Ran Xiaoa, John Michael Tobinb, Meiqin Zhaa, Yunlong Houa, Jun Hec, Filipe Vilela*b, Zhengtao Xu*a

      • a Department of Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong
      • b School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, UK
      • c School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, China

      We report a highly recyclable, 2D aromatic framework that offers a unique and versatile combination of photocatalytic activity and heavy metal uptake capability, as well as other attributes crucial for green and sustainable development technologies. The graphene-like open structure consists of fused tritopic aromatic building blocks (i.e., hexahydroxytriphenylene and hexaazatrinaphthylene) that can be assembled from readily available industrial materials without the need for transition metal catalysts. Besides fast and strong binding for Pb(II) ions (e.g., removing aqueous Pb ions below the drinkable limit within minutes), the alkaline N-heterocycle units of the robust and porous host are able to quantitatively catalyse Knoevenagel reactions in water. Furthermore, the fused donor–acceptor aromatic π-systems enable environmentally friendly photoredox catalysis (PRC) utilizing the safe and abundant visible light in a commercial flow reactor. Also discussed is a new metric for benchmarking the kinetic performance of sorbents in the context of heavy metal removal from drinking water.

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      A novel micro-flow system under microwave irradiation for continuous synthesis of 1, 4-dihydropyridines in the absence of solvents via Hantzsch reaction

      Wei Hea,b, Zheng Fangb, Kai Zhangb, Tao Tua, Niuniu Lvb, Chuanhong Qiub, Kai Guob,c

      • a Department of Chemistry, Fudan University, No. 220 Handan Road, Shanghai, 200433, PR China
      • b College of Biotechnology and Pharmaceutical Engineering, Nanjing Technology University, No. 30 Puzhu South Road, Nanjing, 211816, PR China
      • c State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Technology University, No. 30 Puzhu South Road, Nanjing, 211816, PR China

      γ-Fe2O3 nanoparticles were synthesized in the valve-assisted micromixer. The resulting nanoparticles were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM). In the packed bed flow reactor, the investigation concerning the comparison of different heating methods demonstrated that microwave irradiation displayed the best reaction efficiency compared with air heating and oil-bath heating. A novel micro-flow system under microwave irradiation was designed and employed in the condensation of aldehyde, ethyl acetoacetate and ammonia. Under optimized conditions, Hantzsch reaction conducted well, resulting in a yield of 98.7% and excellent selectivity. In addition, this novel process worked well for other substrates.

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      Methanolysis of epoxidized soybean oil in continuous flow conditions

      Vincenzo Pantonea, Amelita Grazia Laurensab, Cosimo Annesec, Francesco Fracassib, Caterina Fuscob, Angelo Naccib,c, Antonella Russoa, Lucia D’Accoltib,c

      • a Greenswitch s.r.l., Ferrandina MT, Italy
      • b Dipartimento di Chimica, Università di Bari Aldo Moro, Via E. Orabona 4, 70126 Bari, Italy
      • c ICCOM-CNR, SS Bari, Via E. Orabona 4, 70126 Bari, Italy

      Bio-polyols synthesized from vegetables oils are a great alternative to petrochemical polyols for polyurethanes industry. The simplest approach to bio-polyols synthesis involves epoxidation of carbon–carbon double bond of unsaturated fatty ester moieties and subsequent epoxide ring-opening by nucleophilic reagents. In order to improve the latter process by increasing both productivity and product quality, the advantages of flow chemistry were exploited, such as facile automation, reproducibility, improved safety and process reliability, investigating for the first time in the literature the methanolysis reaction of epoxidized soybean oil (ESO) in a continuous flow mode.

      Compared with batch reaction, flow mode allowed the cut of the reaction time from 30 min to 2 min, and the reduction of catalyst concentration by an order of magnitude, which brought significant benefits in terms of cost efficiency and eco-sustainability, rendering the method suitable for industrial applications.

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      Visible-light-induced trifluoromethylation of highly functionalized arenes and heteroarenes in continuous flow

      Irini Abdiaja, Cecilia Bottecchiab, Jesus Alcazar*a, Timothy Noёl*b

      • a Janssen Research & Development, Jarama 75A, 45007 Toledo, Spain
      • b Department of Chemical Engineering and Chemistry, Micro Flow Chemistry & Process Technology, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands

      We report a continuous-flow protocol for the trifluoromethylation of arenes, heteroarenes, and benzofused heterocycles. This photoredox methodology relies on the use of solid sodium trifluoromethanesulfinate (CF3SO2Na) as the trifluoromethylating agent and the iridium complex [Ir{dF(CF3)ppy}2](dtbpy)]PF6 as the photoredox catalyst. A diverse set of highly functionalized heterocycles proved compatible with the methodology, and moderate to good yields were obtained within 30 minutes of residence time.

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      Continuous preparation and use of dibromoformaldoxime as a reactive intermediate for the synthesis of 3- bromoisoxazolines

      We report the multistep continuous process for the preparation of dibromoformaldoxime (DBFO) as a precursor to generate bromoisoxazolines. We also report process improvements that afford a productivity of over 620 mmol h-1 of DBFO.

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      Chemoenzymatic synthesis in flow reactors: a rapid and convenient preparation of captopril

      Dr. Valerio De Vitis1, Dr. Federica Dall'Oglio1, Dr. Andrea Pinto2, Prof. Carlo De Micheli2, Prof. Francesco Molinari1, Prof. Paola Conti2, Dr. Diego Romano1, Dr. Lucia Tamborini2

      • 1 Department of Food Environmental and Nutritional Science, University of Milan, Milan, Italy
      • 2 Department of Pharmaceutical Sciences, University of Milan, Milan, Italy

      The chemoenzymatic flow synthesis of enantiomerically pure captopril, a widely used antihypertensive drug, is accomplished starting from simple, inexpensive, and readily available reagents. The first step is a heterogeneous biocatalyzed regio- and stereoselective oxidation of cheap prochiral 2-methyl-1,3-propandiol, performed in flow using immobilized whole cells of Acetobacter aceti MIM 2000/28, thus avoiding the use of aggressive and environmentally harmful chemical oxidants. The isolation of the highly hydrophilic intermediate (R)-3-hydroxy-2-methylpropanoic acid is achieved in-line by using a catch-and-release strategy. Then, three sequential high-throughput chemical steps lead to the isolation of captopril in only 75 min. In-line quenching and liquid–liquid separation enable breaks in the workflow and other manipulations to be avoided.

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      Preparation of polyfunctional diorgano-magnesium and – zinc reagents using in situ trapping halogen-lithium exchange of highly functionalized (hetero)aryl halides in continuous flow

      Marthe Ketels, Maximilian Andreas Ganiek, Niels Weidmann, Paul Knochel

      • LMU München, Department of Chemistry, München, Germany

      We report a halogen-lithium exchange performed in the presence of various metal salts (ZnCl2, MgCl2·LiCl) on a broad range of sensitive bromo- or iodo-(hetero)arenes using BuLi or PhLi as exchange reagent and a commercially available continuous flow setup. The resulting diarylmagnesium or diarylzinc species were trapped with various electrophiles resulting in the formation of polyfunctional (hetero)arenes in high yields. This methodology enabled the functionalization of (hetero)arenes containing highly sensitive groups such as an isothiocyanate, nitro, azide or ester. A straightforward scale-up was possible without further optimization.

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      Flow assisted synthesis: a key fragment of SR 142948A

      Matthew Oliver Kitching, Olivia E Dixon, Marcus Baumann, Ian Richard Baxendale

      • University of Durham, Chemistry, Durham, UK

      We report a series of multi-step flow operations to deliver an advanced hydrazine intermediate used in the assembly of the Neurotensin modulator SR142948A. Several new reactor configurations have enabled chemical transformations that would be otherwise difficult or dangerous to perform at scale. Overall the flow approach has allowed the preparation of kilogram quantities of the required hydrazine via a short and efficient route.

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      Singlet oxygen oxidations in homogeneous continuous flow using a gas–liquid membrane reactor

      Antonia Kouridaki, Kevin Huvaere

      • EcoSynth NV, Industrielaan 12, 9800 Deinze, Belgium

      A flow chemistry reactor system for scalable photooxygenation reactions was developed using a gas–liquid reactor as key feature. Herein oxygen gas is dissolved under pressure in the reaction mixture to give a homogeneous flow regime prior to irradiation. The system enables safe mass transport of oxygen in an accurate manner simply by adjusting liquid flow rate, membrane temperature, and gas pressure as concluded after characterization of reactor behaviour. Quantification of oxygen supply as function of liquid flow rate and membrane temperature showed that 50 mM and 58 mM of oxygen were supplied to methanol and acetonitrile at 1 mL min−1 flow rate and 110 °C membrane temperature. With 100 mM measured at 90 °C, dichloromethane was most effective for oxygen uptake. Photooxidation of a model system, the furan derivative ethyl 3-(2-furyl)propanoate, was elaborated to validate the system for singlet oxygen chemistry, with reactor parameters being further optimized for maximum conversion. Scope of the system was demonstrated by performing a set of representative photochemical oxidations, including reaction with citronellol as first step in the synthesis of rose oxide.

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      A convenient, mild and green synthesis of NH-sulfoximines in flow reactors

      Leonardo Degennaro1, Arianna Tota1, Sonia De Angelis1, Michael Andresini1, Cosimo Cardellicchio2, Maria Annunziata Capozzi1, Giuseppe Romanazzi3, Renzo Luisi1

      • 1 University of Bari, Department of Pharmacy - Drug Sciences, Bari, Italy
      • 2 CNR ICCOM, Department of Chemistry, Bari, Italy
      • 3 Politecnico di Bari, DICATECh, Bari, Italy

      NH-Sulfoximines are emerging as useful and important targets in drug discovery and synthetic organic chemistry. We report herein the development of an efficient, convenient, and sustainable continuous flow strategy, for the direct straightforward preparation of NH-sulfoximines using sulfides or sulfoxides as suitable starting material. The flow process uses PhI(OAc)2 as the oxidant and aqueous solutions of ammonia as the N-source. The scope of the reaction has been demonstrated by using several substituted sulfides and sulfoxides including enantioenriched and biologically relevant starting materials. The flow strategy was found more convenient with respect to conventional batch processing.

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      A continuous flow method for the desulfurization of substituted thioimidazoles applied to the synthesis of new etomidate derivatives

      Marcus Baumann, Ian R Baxendale

      • Durham University, Department of Chemistry, Durham, UK

      A simple yet robust flow set-up for the efficient desulfurization of a series of thioimidazoles is presented generating the corresponding imidazole derivatives in high yields. The strategic choice of peristaltic over piston pumps allowed reliable delivery of the heterogeneous stream of thioimidazole substrate into a T-piece where it reacted with NaNO2 in the presence of acetic acid. This approach enabled the controlled and safe formation of the reactive nitrosonium species without uncontrolled exposure to hazardous nitrous oxide by-products as observed in related batch protocols. The value of the resulting imidazole products was further demonstrated by their conversion into various esters representing new derivatives of the known analgesic etomidate via an efficient one pot Corey-Gilman-Ganem oxidation procedure.

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      High throughput photo-oxidations in a packed bed reactor system

      Caleb J. Kong, Daniel Fisher, Bimbisar K. Desai,. Yuan Yang, Saeed Ahmad, Katherine Belecki, B. Frank Gupton

      • Department of Chemistry and Department of Chemical and Life Science Engineering, Virginia Commonwealth University, 601 W. Main St. Richmond, VA 23220, USA

      The efficiency gains produced by continuous-flow systems in conducting photochemical transformations have been extensively demonstrated. Recently, these systems have been used in developing safe and efficient methods for photo-oxidations using singlet oxygen generated by photosensitizers. Much of the previous work has focused on the use of homogeneous photocatalysts. The development of a unique, packed-bed photoreactor system using immobilized rose bengal expands these capabilities as this robust photocatalyst allows access to and elaboration from these highly useful building blocks without the need for further purification. With this platform we were able to demonstrate a wide scope of singlet oxygen ene, [4+2] cycloadditions and heteroatom oxidations. Furthermore, we applied this method as a strategic element in the synthesis of the high-volume antimalarial artemisinin.

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      Phase separation macrocyclization in a complex pharmaceutical setting: application toward the synthesis of vaniprevir

      Eric Godin, Anne-Catherine Bédard, Michael Raymond, Shawn K. Collins*

      • Département de Chimie, Centre for Green Chemistry and Catalysis, Université de Montréal, CP 6128 Station Downtown, Montréal, Québec, H3C 3J7 Canada

      A phase separation/continuous flow strategy employing an oxidative Glaser–Hay coupling of alkynes has been applied toward the synthesis of the macrocyclic core of complex pharmaceutical vaniprevir. The phase separation/continuous flow strategy afforded similar yields at 100–500 times the concentration and at shorter reaction times than common slow addition/high dilution techniques. In addition, dendritic PEG cosolvents were employed in the phase separation strategy for the first time and shown to allow productive macrocyclization at concentrations up to 200 mM.

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      Grignard reagents on a tab: direct magnesium insertion under flow conditions

      Lena Huck†,‡, Antonio de la Hoz, Angel Díaz-Ortiz, Jesus Alcázar

      • Janssen Research and Development, Janssen-Cilag, S.A., C/Jarama 75, 45007 Toledo, Spain
      • Facultad de Ciencias Químicas, Universidad de Castilla-La Mancha, 13071 Ciudad Real, Spain

      An on-demand preparation of organomagnesium reagents is presented using a new flow protocol. The risks associated with the activation of magnesium are circumvented by a new on-column initiation procedure. Required amounts of solutions with a precise titration were obtained. Telescoped flow or batch reactions allow access to a diverse set of functional groups.

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      Co-production of HMF and gluconic acid from sucrose by chemo-enzymatic method

      Hongli Wu, Ting Huang, Fei Cao, Qiaogen Zou, Ping Wei, Pingkai Ouyang

      • College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, 30 South Puzhu Road, Nanjing 211816 PR China

      Co-production of multi-products is one of the core principles of chemical industry, and it is also an important way to improve the atom economy. Herein, we proposed an approach to co-producing two valuable platform compounds, gluconic acid (GA) and 5-hydroxymethyl furfural (HMF), from sucrose by successive hydrolysis, oxidation and dehydration. In the enzymatic oxidation step, only glucose was oxidized to GA, meanwhile fructose was 100% retained. In the further biphasic dehydration system, only fructose was converted into HMF, whereas GA was maintained with over 95% recovery. After three reactions, the yields of HMF and GA were respectively 42.5% and 48% when the initial feedstock of sucrose was 200 g/L. Two products were easily separated because GA was completely existed in aqueous phase, and HMF was mainly in organic phase. In the whole process, only commercial enzymes and mineral acid were used instead of self-made catalysts.

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      Efficient synthesis of 5-(chloromethyl) furfural (CMF) from high fructose corn syrup (HFCS) using continuous flow processing

      T. M. Kohla, B. Bizeta, P. Kevana, C. Sellwooda, J. Tsanaktsidisa, C. H. Hornunga

      • a CSIRO Manufacturing Flagship, Bag 10, Clayton South, Australia

      Using continuous flow processing the synthesis of 5-(chloromethyl) furfural (CMF) from both solid sugars and high fructose corn syrup (HFCS) was achieved. The use of HFCS allows for a convenient liquid sugar feedstock, which in turn through our improved three pump system, allows for production of CMF with no additional handling of stock solutions. Extensive reaction optimisation was also carried out with large increases in reaction efficiency achieved over existing batch processes.

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      Barbier continuous flow preparation and reactions of carbamoyllithiums for nucleophilic amidation

      Maximilian Andreas Ganiek, Matthias Richard Becker, Guillaume Berionni, Hendrik Zipse, Paul Knochel

      • LMU München, Department of Chemistry, München, Germany

      An ambient temperature continuous flow method for nucleophilic amidation and thioamidation is described. Deprotonation of formamides by lithium diisopropylamine (LDA) affords carbamoyllithium intermediates that are quenched in situ with various electrophiles such as ketones, allyl bromides, Weinreb and morpholino amides. The nature of the reactive lithium intermediates and the thermodynamics of the metalation were further investigated by ab initio calculations and kinetic experiments.

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      Polymer-supported photosensitizers for oxidative organic transformations in flow and under visible light irradiation

      John M. Tobin, Timothy J. D. McCabe, Andrew W. Prentice, Sarah Holzer, Gareth O. Lloyd, Martin J. Paterson, Valeria Arrighi, Peter A. G. Cormack, Filipe Vilela

      • School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS Scotland, United Kingdom
      • WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL Scotland, United Kingdom

      A 2,1,3-benzothiadiazole (BTZ)-based vinyl cross-linker was synthesized and copolymerized with large excesses of styrene using free radical polymerization to deliver heterogeneous triplet photosensitizers in three distinct physical formats: gels, beads, and monoliths. These photosensitizers were employed for the production of singlet oxygen (1O2) and for the aerobic hydroxylation of arylboronic acids via superoxide radical anion (O2•–), whereby the materials demonstrated good chemical and light stability. BTZ-containing beads and monoliths were exploited as photosensitizers in a commercial flow reactor, and 1O2 production was also demonstrated using direct sunlight irradiation, with a conversion rate comparable to the rates achieved when a 420 nm LED module is used as the source of photons.

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      Direct valorisation of waste cocoa butter triglycerides via catalytic epoxidation, ring-opening and polymerisation

      Dorota D Plazaa, Vinzent Strobelb, Parminder Kaur KS Heerb, Andrew B Sellarsd, Seng-Soi Hoongd, Andrew J Clarkd, Alexei A Lapkinb

      • a School of Engineering, University of Warwick, Coventry, UK
      • b Department of Chemical Engineering and Biotechnology, University of Cambridge, UK
      • c Aachener Verfahrenstechnik – Process Systems Engineering, RWTH Aachen University, Aachen, Germany
      • d Department of Chemistry, University of Warwick, Coventry, UK

      Development of circular economy requires significant advances in the technologies for valorisation of waste, as waste becomes new feedstock. Food waste is a particularly important feedstock, containing large variation of complex chemical functionality. Although most food waste sources are complex mixtures, waste from food processing, no longer suitable for the human food chain, may also represent relatively clean materials. One such material requiring valorisation is cocoa butter.

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      Hydrogen sulfide chemistry in continuous flow: Efficient synthesis of 2-oxopropanethioamide

      David Cantillo1,2, Phillip A. Inglesby3, Alistair Boyd3, Oliver Kappe1,2

      • 1 Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria
      • 2 Research Center Pharmaceutical Engineering (RCPE), Inffeldgasse 13, 8010 Graz, Austria
      • 3 AstraZeneca, Silk Road Business Park, Macclesfield, SK10 2NA, United Kingdom

      A safe and scalable procedure for the synthesis of 2-oxopropanethioamide, an intermediate in the synthesis of a potent β-secretase (BACE-1) inhibitor, from the reaction of acetyl cyanide with hydrogen sulfide gas under continuous-flow conditions has been developed. The toxic gas could be accurately dosed using a mass-flow controller or a peristaltic pump. The reaction proceeded smoothly at room temperature in the presence of a small amount of triethylamine as basic catalyst. After a residence time of 15 min, excellent yield (96%) and purity (>99%) were obtained for the target compound. The high reaction selectivity permitted a simple workup procedure consisting of evaporation of all volatiles.

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

      Chinmay A. Shukla1,2, Amol A. Kulkarni1,2

      • 1 Academy of Scientific and Innovative Research (AcSIR), CSIR-National Chemical Laboratory (NCL) Campus, Pune 411008, India
      • 2 Chem. Eng. & Proc. Dev. Div., CSIR-National Chemical Laboratory, Dr. Homi Bhaba Road, Pashan, Pune 411008, India

      The implementation of automation in the multistep flow synthesis is essential for transforming laboratory-scale chemistry into a reliable industrial process. In this review, we briefly introduce the role of automation based on its application in synthesis viz. Auto sampling and inline monitoring, optimization and process control. Subsequently, we have critically reviewed a few multistep flow synthesis and suggested a possible control strategy to be implemented so that it helps to reliably transfer the laboratory-scale synthesis strategy to a pilot scale at its optimum conditions. Due to the vast literature in multistep synthesis, we have classified the literature and have identified the case studies based on few criteria viz. Type of reaction, heating methods, processes involving in-line separation units, telescopic synthesis, processes involving in-line quenching and process with the smallest time scale of operation. This classification will cover the broader range in the multistep synthesis literature.

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      Utilizing on‐and off‐line monitoring tools to follow a kinetic resolution step during flow synthesis

      Kathleen A. Farley, Usa Reilly, Dennis P. Anderson, Brian P. Boscoe, Mark W. Bundesmann, David A. Foley, Manjinder S. Lall, Chao Li, Matthew R. Reese, Jiangli Yan

      • Medicinal Sciences, Pfizer Worldwide Research and Development, Groton, CT, United States

      In situ reaction monitoring tools offer the ability to track the progress of a synthetic reaction in real time to facilitate reaction optimization and provide kinetic/mechanistic insight. Herein, we report the utilization of flow NMR, flow IR, and other off-line spectroscopy tools to monitor the progress of a flow chemistry reaction. The on-line and off-line tools were selected to facilitate the stereoselective kinetic resolution of a key racemic monomer, which lacked a chromophore, making conventional reaction monitoring difficult.

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      Flow Synthesis of Cyclobutanones via [2+2] Cycloaddition of Keteneiminium Salts and Ethylene Gas

      Claudio Battilocchioa, Grazia Iannuccia, Shiyi Wanga, Edouard Godineaub, Amandine Kriegerb, Alain De Mesmaekerb, Steven V Ley*a

      • a Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, UK
      • b Syngenta Crop Protection AG, Crop Protection Research, Schaffhauserstrasse 101, CH-4332, Switzerland

      A flow chemistry process for the synthesis of 2-substituted cyclobutanones, via [2+2] cycloaddition of keteneiminium salts and ethylene gas, is reported. Our approach uses rapid and mild reaction conditions to access a diverse array of products with good to excellent yield, alongside a good level of functional group compatibility.

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      Continuous Flow α-Arylation of N,N-Dialkylhydrazones under Visible-Light Photoredox Catalysis

      • Juan A. Vega
      • José Manuel Alonso
      • Gabriela Méndez
      • Myriam Ciordia
      • Francisca Delgado
      • Andrés A. Trabanco
      • Neuroscience Medicinal Chemistry, Janssen Research & Development, Jarama 75A, 45007 Toledo, Spain

      The first direct α-arylation of aldehyde-derived N,N-dialkylhydrazones with electron deficient aryl and heteroaryl cyanides under visible-light photoredox catalysis has been developed. Structurally complex α,α′-diaryl-N,N-cycloalkylhydrazones were obtained in moderate yields by repetition of the direct arylation protocol. A continuous-flow procedure for the preparation of α-aryl-N,N-dialkylhydrazones on a multigram scale has also been established.

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      Utilization of flow chemistry in catalysis: New avenues for the selective synthesis of Bis(indolyl)methanes

      • Swapna S. Mohapatraa,b
      • Zoe E. Wilsona
      • Sujit Royb
      • Steven V. Leya
      • a Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
      • b Organometallics & Catalysis Laboratory, School of Basic Sciences, Indian Institute of Technology, Bhubaneswar 751013, India

      Flow chemistry enables the preparation of bis(indolyl)methanes from various indoles and structurally divergent aldehydes using Sc(OTf)3 catalysis. The reaction is regioselective for C-3 functionalization of the indoles, occurring over short reaction times allowing for rapid investigation of scope with straightforward work up facilitating product isolation.

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

      Ananda Herath, Nicholas D. P. Cosford

      • Cancer Metabolism & Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA

      A versatile continuous-flow synthesis of highly functionalized 1,2,4-oxadiazoles starting from carboxylic acids is reported. This process was applied to the multistep synthesis of imidazo[1,2-a]pyridin-2-yl-1,2,4-oxadiazoles, using a three reactor, multistep continuous-flow system without isolation of intermediates. This continuous-flow method was successfully combined with a single-step liquid–liquid microextraction unit to remove high boiling point polar solvents and impurities and provides the target compounds in high purity with excellent overall yields.

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      Preparation of Forced Gradient Copolymers Using Tube-in-Tube Continuous Flow Reactors

      Simon Saubern, Xuan Nguyen, Van Nguyen, James Gardiner, John Tsanaktsidis, John Chiefari

      • CSIRO Manufacturing, Clayton, VIC, Australia

      The preparation of forced gradient polymers has received considerable attention using batch reactors, while the preparation of usable quantities of forced gradient copolymers using continuous flow reactors has been hampered by the need to vary the composition of the monomer feedstock continuously during the reaction. A reactor that allows for addition of a monomer feedstock continuously at all points along the length of the reactor tubing allows for the preparation of forced gradient copolymers in continuous flow reactors, allowing for the scale-up and bulk preparation of these polymers. This study reports here the initial investigation of preparing forced gradient copolymers using the reversible addition–fragmentation chain transfer methodology in tube-in-tube continuous flow reactors.

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      A Continuous Flow Synthesis and Derivatization of 1,2,4-Thiadiazoles

      • Marcus Baumann
      • Ian R. Baxendale
      • Department of Chemistry, University of Durham, South Road, DH1 3LE Durham, United Kingdom.

      A continuous flow process is presented that enables the efficient synthesis and derivatization of 1,2,4-thiadiazole heterocycles. Special attention was given to the safe handling of the versatile yet hazardous trichloromethane sulfenylchloride reagent including its in-line quenching in order to eliminate malodourous and corrosive by-products. Based on this flow method gram quantities of 5-chloro-3-phenyl-1,2,4-thiadiazole were safely prepared allowing for further elaboration of this valuable building block by reaction with different nitrogen-, sulfur- and oxygen-based nucleophiles. This synthetic approach was subsequently applied to generate a series of bromophenyl-5-chloro-1,2,4-thiadiazoles providing a valuable entry towards further structural diversification on this important heterocyclic scaffold.

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      Self-Optimisation and Model-Based Design of Experiments for Developing a C–H Activation Flow Process

      Alexander Echtermeyer1,2, Yehia Amar2, Jacek Zakrzewski2, Alexei Lapkin2

      • 1 Aachener Verfahrenstechnik – Process Systems Engineering, RWTH Aachen University, Aachen, Germany
      • 2 Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, United Kingdom

      A recently described C(sp3)–H activation reaction to synthesise aziridines was used as a model reaction to demonstrate the methodology of developing a process model using model-based design of experiments (MBDoE) and self-optimisation approaches in flow. The two approaches are compared in terms of experimental efficiency. The self-optimisation approach required the least number of experiments to reach the specified objectives of cost and product yield, whereas the MBDoE approach enabled a rapid generation of a process model.

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

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

      • CSIRO Manufacturing, Bag 10, Clayton South, Victoria 3169, Australia

      This work describes the Diels–Alder reaction of the naturally occurring substituted butadiene, myrcene, with a range of 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 approach provides a facile alternative scale-up route to conventional batch processing, and it helps to intensify the synthesis protocol by applying higher reaction temperatures and shorter reaction times.

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      Active Site-Mapping of Xylan-Deconstructing Enzymes with Arabinoxylan Oligosaccharides Produced by Automated Glycan Assembly

      Deborah Senf, Colin Ruprecht, Goswinus de Kruijff, Sebastian Simonetti, Frank Schuhmacher, Peter Seeberger, Fabian Pfrengle

      • Max-Planck-Institute of Colloids and Interfaces, Biomolecular Systems, Potsdam, Germany

      Xylan-degrading enzymes are crucial for the deconstruction of hemicellulosic biomass, making the hydrolysis products available for various industrial applications such as biofuel production. To determine the substrate specificities of these enzymes, we prepared a collection of complex xylan oligosaccharides by automated glycan assembly. Seven differentially protected building blocks provided the basis for the modular assembly of 2-substituted, 3-substituted, and 2-/3-substituted arabino- and glucuronoxylan oligosaccharides. Elongation of the xylan backbone relied on iterative additions of C4-fluorenylmethoxylcarbonyl (Fmoc) protected xylose building blocks to a linker-functionalized resin. Arabinofuranose and glucuronic acid residues have been selectively attached to the backbone using fully orthogonal 2-(methyl)naphthyl (Nap) and 2-(azidomethyl)benzoyl (Azmb) protecting groups at the C2- and C3-hydroxyls of the xylose building blocks. The arabinoxylan oligosaccharides are excellent tools to map the active site of glycosyl hydrolases involved in xylan deconstruction. The substrate specificities of several xylanases and arabinofuranosidases were determined by analyzing the digestion products after incubation of the oligosaccharides with glycosyl hydrolases.

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      Mixed-Linkage Glucan Oligosaccharides Produced by Automated Glycan Assembly Serve as Tools to Determine the Substrate Specificity of Lichenase

      Pietro Dallabernardina, Frank Schuhmacher, Peter H Seeberger, Fabian Pfrengle

      • Max-Planck-Institute of Colloids and Interfaces, Biomolecular Systems, Potsdam, Germany

      The mixed-linkage (1→3),(1→4)-D-glucan (MLG) specific glycosyl hydrolase lichenase is an important biochemical tool for the structural characterization of MLGs. It holds potential for application in the brewery, animal feed, and biofuel industries. Several defined MLG oligosaccharides obtained by automated glycan assembly are used to analyze the substrate specificities of Bacillus subtilis lichenase. Two glucose building blocks (BBs), equipped with a temporary Fmoc protecting group in the C-3 or C-4 position, served to assemble different oligosaccharides using an automated oligosaccharide synthesizer. Light-induced cleavage of the glycan products from the solid support followed by global deprotection provided seven MLG oligosaccharides of different length and connectivity. After incubation of the MLG oligosaccharides with lichenase, the digestion products were analyzed by HPLC-MS. These digestion experiments provided insights into the enzyme’s active site that is in line with other recent evidence suggesting that the substrate specificity of lichenases has to be reconsidered. These results demonstrate that synthetic MLG oligosaccharides are useful tools to analyse mixed-linkage β-glucanases.

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      Improving the throughput of batch photochemical reactions using flow: Dual photoredox and nickel catalysis in flow for C(sp2) C(sp3) cross-coupling

      • Irini Abdiaj, Jesús Alcázar
      • Janssen Research and Development, Janssen-Cilag, S.A., C/Jarama 75, 45007 Toledo, Spain

      We report herein the transfer of dual photoredox and nickel catalysis for C(sp2)single bondC(sp3) cross coupling form batch to flow. This new procedure clearly improves the scalability of the previous batch reaction by the reactor’s size and operating time reduction, and allows the preparation of interesting compounds for drug discovery in multigram amounts.

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      Synthesis of Cycloalkyl Substituted 7-Azaindoles via Photoredox Nickel Dual Catalytic Cross-Coupling in Batch and Continuous Flow

      • Natalie Palaychuk, Travis J. DeLano, Michael J. Boyd, Jeremy Green, and Upul K. Bandarage
      • Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, Massachusetts 02210, United States

      An efficient photoredox/Ni dual catalytic Csp2–Csp3 cross-coupling protocol in a continuous-flow regime to synthesize a variety of regioisomeric cycloalkyl substituted 7-azaindoles has been developed. These transformations proceed efficiently under mild conditions (blue LED light irradiation at 30 °C over 40 min residence time in mixed solvent systems). Reactions are easy to perform and afford most of the desired 2-, 3-, 4-, 5-, and 6-cycloalkyl substituted 7-azaindoles in moderate-to-good yield.

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      Acridinium-Based Photocatalysts: A Sustainable Option in Photoredox Catalysis

      • Amruta Joshi-Pangu
      • François Lévesque
      • Hudson G. Roth
      • Steven F. Oliver
      • Louis-Charles Campeau
      • David Nicewicz
      • Daniel A. DiRocco
      • Process Research & Development, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States
      • Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States

      The emergence of visible light photoredox catalysis has enabled the productive use of lower energy radiation, leading to highly selective reaction platforms. Polypyridyl complexes of iridium and ruthenium have served as popular photocatalysts in recent years due to their long excited state lifetimes and useful redox windows, leading to the development of diverse photoredox-catalyzed transformations. The low abundances of Ir and Ru in the earth’s crust and, hence, cost make these catalysts nonsustainable and have limited their application in industrial-scale manufacturing. Herein, we report a series of novel acridinium salts as alternatives to iridium photoredox catalysts and show their comparability to the ubiquitous [Ir(dF-CF3-ppy)2(dtbpy)](PF6).

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      Halogenation of organic compounds using continuous flow and microreactor technology

      • David Cantilloab
      • C. Oliver Kappe*ab
      • a Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, Graz, Austria
      • b Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria

      The halogenation of organic substrates is one the most important transformations in organic synthesis. The most straightforward, inexpensive and atom economic halogenations involve the use of elemental halogens (X2) or hydrogen halides (HX). However, X2 and HX reagents are highly reactive, toxic and corrosive materials. Halogenations using these reagents are usually very fast and exothermic reactions, in which selectivity issues occur. Using continuous flow chemistry halogenations involving X2 and HX can be performed in a safe and controllable manner. Reagents can be accurately dosed even for gas/liquid reactions, and exotherms are easily controlled. Hazardous chemicals can be readily quenched in line avoiding any undesired exposures and significantly enhancing the process safety.

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      Application of the Photoredox Coupling of Trifluoroborates and Aryl Bromides to Analog Generation Using Continuous Flow

      • Travis J. DeLano, Upul K. Bandarage, Natalie Palaychuk, Jeremy Green, and Michael J. Boyd
      • Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, Massachusetts 02210, United States

      A method for the coupling of aryl bromides with potassium alkyl trifluoroborates, via nickel/photoredox dual catalysis, has been developed for use in continuous flow. This operationally simple protocol is able to form Csp3–Csp2 bonds with significantly reduced reaction times and a broader substrate scope than when conducted in batch. The utility of this method for rapid analog synthesis has been demonstrated by the synthesis of a small library of alkyl-substituted quinazolines.

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      Design and Development of Pd-catalyzed Aerobic N-Demethylation Strategies for the Synthesis of Noroxymorphone in Continuous Flow Mode

      Bernhard Gutmanna,b, David Cantilloa,b, Ulrich Weiglc, D Phillip Coxd, C. Oliver Kappea,b

      • a,b Institute of Chemistry, University of Graz, Nawi Graz, Heinrichstrasse 28, 8010 Graz, Austria and Research Center Pharmaceutical Engineering (RCPE), Inffeldgasse 13, 8010 Graz, Austria
      • c Cilag AG, Hochstrasse 201, 8200 Schaffhausen, Switzerland
      • d Noramco Inc., 503 Carr Road, Suite 200, Wilmington, DE 19809, USA

      Strategies for the generation of noroxymorphone from 14-hydroxymorphinone are presented. Noroxymorphone is the key intermediate in the synthesis of various opioid antagonists, including naloxone, naltrexone and nalmefene, as well as mixed agonists-antagonists like nalbuphine. The transformation requires removal of the N-methyl group from the naturally occurring opiates and a double bond hydrogenation. The pivotal reaction step thereby is a N-methyl oxidation with colloidal palladium(0) as catalyst and pure oxygen as terminal oxidant. The reaction produces a 1,3-oxazolidine intermediate, which can be readily hydrolyzed to the corresponding secondary amine. Different reaction sequences and various phenol protection groups were explored. The most direct route consumes only H2, O2 and H2O as stoichiometric reagents and produces only H2O as by-product. Challenges inherent in gas-liquid reactions with oxygen as oxidant were addressed by developing a continuous flow process.

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      γ-Glutamyl-dipeptides: Easy tools to rapidly probe the stereoelectronic properties of the ionotropic glutamate receptor binding pocket

      • Lucia Tamborinia
      • Veronica Nicosiaa
      • Paola Contia
      • Federica Dall'Oglioa
      • Carlo De Michelia
      • Birgitte Nielsenb
      • Anders A. Jensenb
      • Darryl S. Pickeringb
      • Andrea Pintoa
      • a Department of Pharmaceutical Sciences (DISFARM), University of Milan, Via Mangiagalli 25, 20133 Milan, Italy
      • b Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen OE, Denmark

      γ-Glutamyl-dipeptides, built by condensing the distal carboxylate of l-Glu (or d-Glu) onto a series of differently functionalized amino acids, were prepared and used as tools for rapidly probing the stereo-electronic properties of iGluRs, searching for subtype-selective ligands.

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      Expedited access to thieno[3,2-c]quinolin-4(5H)-ones and benzo[h]-1,6-naphthyridin-5(6H)-ones via a continuous flow photocyclization method

      • Y. Fanga
      • G. K. Tranmer*ab
      • * Corresponding author
      • a College of Pharmacy, Faculty of Health Science, University of Manitoba, Winnipeg, Canada
      • b Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, Canada

      A single-step continuous flow method has been developed that gives expedited access to complex heterocycles via an intramolecular photochemical cyclization. Herein we report the first examples of the photochemically-induced generation of thieno[3,2-c]quinolin-4(5H)-ones, 16 examples, and benzo[h]-1,6-naphthyridin-5(6H)-ones, 6 examples. Overall, the continuous flow method provides access to complex heterocycles in two steps from commercially available starting materials in good yields and with greater atom efficiency than traditional batch reactions.

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      A benchtop NMR spectrometer as a tool for monitoring mesoscale continuous-flow organic synthesis: equipment interface and assessment in four organic transformations

      • Cynthia M. Archambaulta
      • Nicholas E. Leadbeater*a
      • * Corresponding author
      • a Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, USA

      An approach is reported for monitoring continuous-flow reactions by means of a low-field benchtop NMR spectrometer. The spectrometer is interfaced with a mesofluidic reactor and used as a tool for optimising four organic transformations, namely an acid-catalysed esterification, a Knoevenagel condensation, a Diels–Alder reaction, and an alkylation. Reactions need to be performed either solvent-free or at relatively high concentration in order to monitor them effectively using the NMR spectrometer, but this allows for the leveraging of one of the key advantages of flow processing, namely process intensification.

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      BODIPY-based conjugated microporous polymers as reusable heterogeneous photosensitisers in a photochemical flow reactor

      • J. M. Tobina
      • J. Liub
      • H. Hayesa
      • M. Demleitnera
      • D. Ellisa
      • V. Arrighia
      • Z. Xu*b
      • F. Vilela*a
      • * Corresponding author
      • a School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, UK
      • b Department of Biology and Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, China

      BODIPY-based conjugated microporous polymers (BDP_CMP and PHTT_BDP) have been synthesised via two distinct methods of assembly: high-yielding Suzuki–Miyaura cross-coupling of BODIPY-containing building blocks, and post-synthetic conversion of an aldehyde-equipped CMP host that was synthesised in the absence of metal-based catalysts. Both approaches yielded BODIPY-based materials featuring a high BET surface area (484–769 m2 g−1) and a bathochromic shift in the maximum light absorbance (520–550 nm). Singlet oxygen production employing the BODIPY-based materials at 530 nm was carried out heterogeneously in a commercial photochemical flow reactor.

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      Reformatsky and Blaise reactions in flow as a tool for drug discovery. One pot diversity oriented synthesis of valuable intermediates and heterocycles

      • L. Hucka,b
      • M. Bertona
      • A. de la Hozb
      • A. Díaz-Ortizb
      • J. Alcázar*a
      • * Corresponding author
      • a Janssen Research and Development, Janssen-Cilag, S.A., C/ Jarama 75, Toledo, Spain
      • b Facultad de Ciencias Químicas, Universidad de Castilla-La Mancha, Ciudad Real, Spain

      The application of Reformatsky and Blaise reactions for the preparation of a diverse set of valuable intermediates and heterocycles in a one-pot protocol is described. To achieve this goal, a greener activation protocol for zinc in flow conditions has been developed to introduce this metal efficiently into α-bromoacetates. The organozinc compounds were added to a diverse set of ketones and nitriles to obtain a wide range of functional groups and heterocyclic systems.

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      Visible light activation of Boronic Esters enables efficient photoredox C(sp2)–C(sp3) cross-couplings in flow

      Fabio Limaa, Dr. Mikhail A. Kabeshova, Dr. Duc N. Trana, Dr. Claudio Battilocchioa, Dr. Joerg Sedelmeierb, Dr. Gottfried Sedelmeierb, Dr. Berthold Schenkelb, S. V. Ley*a

      • * Corresponding author
      • a Department of Chemistry, University of Cambridge, Cambridge, UK
      • b Novartis Pharma AG, Basel, Switzerland

      We report herein a new method for the photoredox activation of boronic esters. Using these reagents, an efficient and high-throughput continuous flow process was developed to perform a dual iridium- and nickel-catalyzed C(sp2)–C(sp3) coupling by circumventing solubility issues associated with potassium trifluoroborate salts. Formation of an adduct with a pyridine-derived Lewis base was found to be essential for the photoredox activation of the boronic esters. Based on these results we were able to develop a further simplified visible light mediated C(sp2)–C(sp3) coupling method using boronic esters and cyano heteroarenes under flow conditions.

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      Engineering chemistry: integrating batch and flow reactions on a single, automated reactor platform

      • D. E. Fitzpatricka
      • S. V. Ley*a
      • * Corresponding author
      • a Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK

      Synthesis chemistry need not be limited to either only batch or only flow; rather, in the future we expect that it will consist of an amalgamation of the best and most appropriate methods. We have therefore devised a single reactor platform to conduct both batch and flow reactions, either singly or in concert, using open source technologies to automate, control and monitor individual processes. We illustrate this concept with the multistep synthesis of 5-methyl-4-propylthiophene-2-carboxylic acid to showcase the utility of this approach in a telescoped manner. Automated downstream processing techniques, consisting of continuous extraction and solvent switching steps, were also included, further freeing the chemist from routine laboratory tasks.

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      Triphenylphosphine-grafted, RAFT-synthesised, porous monoliths as catalysts for Michael addition in flow synthesis

      Kristine J. Barlowa, Victor Bernabeua, Xiaojuan Haoa, Timothy C. Hughesa, Oliver E. Hutta, Anastasios Polyzosa,b, Kathleen A. Turnera, Graeme Moada

      • a CSIRO Manufacturing Flagship, Bag 10, Clayton South, Victoria 3169, Australia
      • b University of Melbourne, School of Chemistry, Parkville, Victoria 3010, Australia

      We describe the preparation and application of triphenylphosphine functional polystyrene-based porous monolithic catalysts for use as flow reactors. RAFT (reversible addition-fragmentation chain transfer)-crosslinking polymerisation of styrene and divinylbenzene provided monoliths which were then functionalized by RAFT “grafting from” polymerisation of 4-styryldiphenylphosphine mediated by the retained thiocarbonylthio functionality. Under the chosen conditions, the retention of the RAFT functionality was proved by chain extension experiments in which the monoliths were five times re-subjected to the grafting conditions. Importantly, the bound triphenylphosphine-functionality was demonstrated to be catalytically active when the monoliths were used as flow reactors in performing Michael addition of 1-hexanethiol to tert-butyl acrylate and of acetyl acetone to diethyl azodicarboxylate. Conversions from reagent to product of up to 77% were achieved. The monoliths were susceptible to oxidation of the phosphine groups most likely caused by adventitious oxygen in the non-degassed reaction medium, but were successfully regenerated by trichlorosilane reduction and reused.

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      Ethyl Lithiodiazoacetate: Extremely unstable intermediate handled efficiently in flow

      Simon T. R. Müllera, Tobias Hokampa, Svenja Ehrmanna, Paul Hellierb, Thomas Wirtha

      • a Cardiff University School of Chemistry Cardiff UK
      • b Parc Industriel de la Chartreuse Pierre Fabre Médicament Castres CEDEX France

      Ethyl diazoacetate(EDA) is one of the most prominent diazo reagents. It is frequently used in metal–carbene-type reactions. However, EDA can also be used as a nucleophile under base catalysis. Whilst the addition of EDA to aldehydes can be performed using organic bases, the addition of EDA to other carbonyl electrophiles requires the use of organometallics such as lithium diisopro-pylamide (LDA). The generated ethyl lithiodiazoacetate is highly reactive and decomposes rapidly, even at low temperatures. Herein, we report a continuous flow protocol that overcomes the problems associated with the instantaneous decomposition of ethyl lithiodiazoacetate. The addition of ethyl lithiodiazoacetate to ketones provides direct access to tertiary diazoalcohols in good yields.

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      A facile hybrid ‘flow and batch’ access to substituted 3,4-dihydro-2H-benzo[b][1,4]oxazinones

      • Andrew J. S. Lina
      • Cecilia C. Russella
      • Jennifer R. Bakera
      • Shelby L. Fraileyab
      • Jennette A. Sakoffc
      • Adam McCluskey*a
      • * Corresponding authors
      • a Chemistry, Centre for Chemical Biology, School of Environmental & Life Sciences, University of Newcastle, University Drive, Callaghan, Australia
      • b Chemical Engineering, Trine University, Angola, 46703 USA
      • c Department of Medical Oncology, Calvary Mater Newcastle Hospital, Waratah, Australia

      We describe a simple flow chemistry approach to libraries of ethyl 3-oxo-2-(substituted-phenylamino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylates (12a–l) and N-ethyl-3-oxo-2-(substituted-phenylamino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamides (13a–l) in 38–87% yields. This scaffold is poorly described in the chemical literature. Screening against a panel of 11 cancer and one normal cell line showed that the amide linked library 13a–l was devoid of toxicity. Whereas the ester linked analogues 12b, 12c, 12g, 12j and 12l were highly cytotoxic with growth inhibition (GI50) values from 0.34 to >50 μM across all cell lines, with the 2-OH-Ph substituted 12l analogue presenting with sub-micromolar potency against the A2780 (ovarian; 0.34 ± 0.04 μM), BEC-2 (glioblastoma; 0.35 ± 0.06 μM), MIA (pancreas; 0.91 ± 0.054 μM) and SMA (murine glioblastoma; 0.77 ± 0.029 μM) carcinoma cell lines. Interestingly, the U87 glioblastoma cell line showed inherent resistance to growth inhibition by all analogues (GI50 32 to >50 μM) while the A2780 cells were highly sensitive (GI50 3.8–0.34 μM), suggesting that the analogues developed herein may be valuable lead compounds for the development of ovarian carcinoma specific cytotoxic agents. The differences in amide versus ester cytotoxicity was consitent with esterase cleaveage to release the cytotoxic warhead.

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      Continuous flow biocatalysis: production and in-line purification of amines by immobilised transaminase from Halomonas elongata

      • Matteo Planchestainera
      • Martina Letizia Contenteab
      • Jennifer Cassidya
      • Francesco Molinarib
      • Lucia Tamborini*c
      • Francesca Paradisi*ad
      • * Corresponding authors
      • a UCD School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland
      • b Department of Food, Environmental and Nutritional Sciences (DeFENS), Università degli studi di Milano, Via Mangiagalli 25, Milan, Italy
      • c Department of Pharmaceutical Sciences (DISFARM), Università degli studi di Milano, Via Mangiagalli 25, Milan, Italy
      • d School of Chemistry, University of Nottingham, University Park, Nottingham, UK

      The continuous flow synthesis of a series of amines was successfully achieved by exploiting the enhanced stability and broad substrate scope of an immobilised transaminase from Halomonas elongata (HEWT). A series of substrates were tested in flow reactors and transformed into the corresponding amines in good to excellent yields. The process was implemented with an integrated in-line purification step for the recovery of the pure amines.

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      A laboratory-scale continuous flow chlorine generator for organic synthesis

      • Franz J. Straussa
      • David Cantillo*ab
      • Javier Guerrac
      • C. Oliver Kappe*ab
      • * Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, Graz, Austria
      • a Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
      • b Crystal Pharma, Gadea Pharmaceutical Group, A Division of AMRI, Parque Tecnológico de Boecillo, Valladolid, Spain

      A simple continuous flow setup for the generation and use of elemental chlorine for organic synthesis has been developed. The chlorine generator is based on the reaction of HCl with NaOCl, generating NaCl and H2O as the only side products. As a proof-of-concept, the reactor has been applied for a variety of chlorinations and oxidations of organic compounds.

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      Continuous processing and efficient in situ reaction monitoring of a hypervalent iodine (III) mediated cyclopropanation using benchtop NMR spectroscopy

      Batool Ahmed-Omer, Eric Sliwinski, John Paul Cerroti, Steven V Ley

      Real-time NMR spectroscopy has proven to be a rapid and an effective monitoring tool to study the hypervalent iodine (III) mediated cyclopropanation. With the ever increasing number of new synthetic methods for carbon-carbon bond formation, the NMR in situ monitoring of reactions is becoming a highly desirable enabling method. In this study, we have demonstrated the versatility of benchtop NMR using inline and online real-time monitoring methods to access mutually complementary information for process understanding, and developed new approaches for real-time monitoring addressing challenges associated with better integration into continuous processes.

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      Aryl amination using ligand-free Ni(II) salts and photoredox catalysis

      Emily B. Corcoran1, Michael T. Pirnot2, Shishi Lin3, Spencer D. Dreher3, Daniel A. DiRocco3, Ian W. Davies3, Stephen L. Buchwald2,*, David W. C. MacMillan1,*

      • 1 Merck Center for Catalysis at Princeton University, Princeton, NJ 08544, USA
      • 2 Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
      • 3 Department of Process Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA

      Over the past two decades, there have been major developments in transition metal–catalyzed aminations of aryl halides to form anilines, a common structure found in drug agents, natural product isolates, and fine chemicals. Many of these approaches have enabled highly efficient and selective coupling through the design of specialized ligands, which facilitate reductive elimination from a destabilized metal center. We postulated that a general and complementary method for carbon–nitrogen bond formation could be developed through the destabilization of a metal amido complex via photoredox catalysis, thus providing an alternative approach to the use of structurally complex ligand systems. Here, we report the development of a distinct mechanistic paradigm for aryl amination using ligand-free nickel(II) salts, in which facile reductive elimination from the nickel metal center is induced via a photoredox-catalyzed electron-transfer event.

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      Catalytic Chan–Lam coupling using a ‘tube-in-tube’ reactor to deliver molecular oxygen as an oxidant

      Carl J. Mallia1, Paul M. Burton2, Alexander M. R. Smith2, Gary C. Walter2, Ian R. Baxendale1

      • 1 Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, United Kingdom
      • 2 Syngenta CP R&D Chemistry, Jealott’s Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom

      A flow system to perform Chan–Lam coupling reactions of various amines and arylboronic acids has been realised employing molecular oxygen as an oxidant for the re-oxidation of the copper catalyst enabling a catalytic process. A tube-in-tube gas reactor has been used to simplify the delivery of the oxygen accelerating the optimisation phase and allowing easy access to elevated pressures. A small exemplification library of heteroaromatic products has been prepared and the process has been shown to be robust over extended reaction times.

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      An approach to the synthesis of 4-aryl and 5-aryl substituted thiazole-2(3H)-thiones employing flow processing

      • Monaem Baltia
      • Shelli A. Millerb
      • Mohamed Lotfi Efrita
      • Nicholas E. Leadbeater*b
      • * Corresponding authors
      • a Université Tunis El Manar, Laboratory of Organic Synthesis and Heterocyclic Chemistry, Faculty of Science of Tunis, Department of Chemistry, 1060 Tunis, Tunisia
      • b Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, USA

      A method for the preparation of 4-aryl and 5-aryl substituted thiazole-2(3H)-thiones is described. Flow processing is employed as a tool, and supported acids and bases used to facilitate both the synthetic strategy and product isolation. The methodology is applicable to a range of substrates.

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      Flow carbonylation of sterically hindered ortho-subsituted iodoarenes

      Carl J. Mallia1, Gary C. Walter2, Ian R. Baxendale1

      • 1 Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, United Kingdom
      • 2 Syngenta CP R&D Chemistry, Jealott’s Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom

      The flow synthesis of ortho-substituted carboxylic acids, using carbon monoxide gas, has been studied for a number of substrates. The optimised conditions make use of a simple catalyst system compromising of triphenylphosphine as the ligand and palladium acetate as the pre-catalyst. Carbon monoxide was introduced via a reverse “tube-in-tube” flow reactor at elevated pressures to give yields of carboxylated products that are much higher than those obtained under normal batch conditions.

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      Exploring flow procedures for diazonium formation

      Te Hu, Ian R. Baxendale and Marcus Baumann*

      • * Department of Chemistry, University of Durham, South Road, Durham DH1 3LE, UK

      The synthesis of diazonium salts is historically an important transformation extensively utilized in dye manufacture. However the highly reactive nature of the diazonium functionality has additionally led to the development of many new reactions including several carbon-carbon bond forming processes. It is therefore highly desirable to determine optimum conditions for the formation of diazonium compounds utilizing the latest processing tools such as flow chemistry to take advantage of the increased safety and continuous manufacturing capabilities. Herein we report a series of flow-based procedures to prepare diazonium salts for subsequent in-situ consumption.

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      Catalytic macrocyclization strategies using continuous flow: formal total synthesis of ivorenolide A

      Mylène de Léséleuc, Eric Godin, Shawn Parisien-Collette, Alexandre Levesque, and Shawn K. Collins*

      • * University of Montréal, Department of Chemistry, Montréal, Canada

      A formal total synthesis of ivorenolide A has been accomplished employing a Z-selective olefin cross metathesis and a macrocyclic Glaser-Hay coupling as key steps. The macrocyclization protocol employed a phase separation/continuous flow manifold whose advantages include catalysis, fast reaction times, high concentrations and facile scale-up.

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      Delivering enhanced efficiency in the synthesis of α-diazosulfoxides by exploiting the process control enabled in flow

      Patrick G. McCaw1, Benjamin J. Deadman1, Anita R. Maguire1,2, Stuart G. Collins1

      • 1 Department of Chemistry, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Cork, Ireland
      • 2 Department of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Cork, Ireland

      Continuous-flow generation of α-diazosulfoxides results in a two- to three-fold increase in yields and decreased reaction times compared to standard batch synthesis methods. These high yielding reactions are enabled by flowing through a bed of polystyrene-supported base (PS-DBU or PS-NMe2) with highly controlled residence times. This engineered solution allows the α-diazosulfoxides to be rapidly synthesized while limiting exposure of the products to basic reaction conditions, which have been found to cause rapid decomposition. In addition to improved yields, this work has the added advantage of ease of processing, increased safety profile, and scale-up potential.

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      The generation of a library of bromodomain-containing protein modulators expedited by continuous flow synthesis

      Paolo Filipponi and Ian R. Baxendale*

      • * Department of Chemistry, University of Durham South Road, Durham, DH1 3LE, United Kingdom

      A continuous flow process delivering key building blocks for a series of BCP modulator libraries is reported. A dynamically mixed flow reactor emerged as a pivotal technology in both synthesis and isolation phases enabling the processing of slurries and suspensions while maintaining high productivity and reliability. Accordingly, the synthesis of common intermediates in flow were employed to further build a pyridazone-based library (36 compounds) aimed at improving lead compound potency and selectivity while further enabling structure-activity relationship studies of a new BCP modulator family.

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      An efficient etherification of Ginkgol biloba extracts with fewer side effects in a micro-flow system

      • Yin-Lin Qina
      • Wei Hea
      • Mei Sub
      • Zheng Fangc
      • Ping-Kai Ouyanga
      • Kai Guoa,d
      • a College of Biotechnology and Pharmaceutical Engineering, Nanjing Technology University, Nanjing 210009, China
      • b Jiangsu Carephar Pharmaceutical Co., Ltd., Nanjing 210014, China
      • c School of Pharmaceutical, Nanjing Technology University, Nanjing 210009, China
      • d State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Technology University, Nanjing 211816, China

      In this study, etherification of ginkgolide B and dimethylaminoethyl chloride hydrochloride was investigated as a model reaction in a micro-flow system (MFS), providing the resulting ethers in high yield with fewer side effects. Meanwhile, this novel process in MFS worked well for other ginkgolides from Ginkgol biloba and halides, giving moderate yields.

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      Continuous-flow synthesis and derivatization of aziridines through palladium-catalyzed C(sp3)−H activation

      Jacek Zakrzewski1, Adam P. Smalley2, Dr. Mikhail A. Kabeshov2, Prof. Matthew J. Gaunt2, Prof. Alexei A. Lapkin1

      • 1 Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK
      • 2 Chemistry Department, University of Cambridge, Cambridge, UK

      A continuous-flow synthesis of aziridines by palla-dium-catalyzed C(sp3)H activation is described. The newflow reaction could be combined with an aziridine-ring-opening reaction to give highly functionalized aliphaticamines through a consecutive process. A predictive mechanis-tic model was developed and used to design the CH activationflow process and illustrates an approach towards first-princi-ples design based on novel catalytic reactions.

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      Metal-free borylation of electron-rich aryl(pseudo)halides under continuous-flow photolytic conditions

      • Kai Chena
      • Man Sing Cheungb
      • Zhenyang Lin*b
      • Pengfei Li*a
      • a Center for Organic Chemistry, Frontier Institute of Science and Technology (FIST) and Frontier Institute of Chemistry, Xi'an Jiaotong University, 99 Yanxiang Road, Xi'an, China
      • b Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, China

      A metal-free borylation reaction of electron-rich aryl chlorides, fluorides, mesylates and phosphates under continuous-flow photolytic conditions is reported. The flow setup was designed to facilitate this process efficiently in comparison with the batch mode. Owing to its unique chemical selectivity, mild reaction conditions, good functional group tolerance and substrate scope, this reaction adds a complementary protocol to the current synthetic methods for boronic acid derivatives. The proposed reaction mechanism involves a photolytically generated triplet aryl cation, and DFT calculations suggest that the borylation product is formed in an anion-mediated single step process passing a minimum energy crossing point.

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      Difluorocarbene addition to alkenes and alkynes in continuous flow

      • Pauline Rullière
      • Patrick Cyr
      • André B. Charette*
      • Université de Montréal, Centre in Green Chemistry and Catalysis, Department of Chemistry, Faculty of Arts and Science, P.O. Box 6128, Station Downtown, Québec, Canada H3C 3J7

      The first in-flow difluorocarbene generation and addition to alkenes and alkynes is reported. The application of continuous flow technology allowed for the controlled generation of difluorocarbene from TMSCF3 and a catalytic quantity of NaI. The in situ generated electrophilic carbene reacts smoothly with a broad range of alkenes and alkynes, allowing the synthesis of the corresponding difluorocyclopropanes and difluorocyclopropenes. The reaction is complete within a 10 min residence time at high reaction concentrations. With a production flow rate of 1 mmol/min, continuous flow chemistry enables scale up of this process in a green, atom-economic, and safe manner.

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      A simple setup for transfer hydrogenations in flow chemistry

      Matthew Hutchings, Thomas Wirth*

      • School of Chemistry, Cardiff University, Cardiff CF10 3AT, UK

      By using a packed-bed reactor with a palladium charcoal catalyst and ammonium formate or triethylsilane as hydrogen/hydride source, various functional groups including nitro groups, azides and alkenes can be efficiently reduced by a transfer hydrogenation process under mild conditions in a simple flow system.

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      A scalable and operationally simple radical trifluoromethylation

      • Joel W. Beatty1
      • James J. Douglas1,2
      • Kevin P. Cole2
      • Corey R. J. Stephenson1
      • 1 Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA
      • 2 Small Molecule Design and Development, Lilly Research Laboratoires, Eli Lilly and Company, Indianapolis, Indiana 46285, USA

      The large number of reagents that have been developed for the synthesis of trifluoromethylated compounds is a testament to the importance of the CF3 group as well as the associated synthetic challenge. Current state-of-the-art reagents for appending the CF3 functionality directly are highly effective; however, their use on preparative scale has minimal precedent because they require multistep synthesis for their preparation, and/or are prohibitively expensive for large-scale application. For a scalable trifluoromethylation methodology, trifluoroacetic acid and its anhydride represent an attractive solution in terms of cost and availability; however, because of the exceedingly high oxidation potential of trifluoroacetate, previous endeavours to use this material as a CF3 source have required the use of highly forcing conditions. Here we report a strategy for the use of trifluoroacetic anhydride for a scalable and operationally simple trifluoromethylation reaction using pyridine N-oxide and photoredox catalysis to affect a facile decarboxylation to the CF3 radical., USA

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      Photoactive and metal-free polyamide-based polymers for water and wastewater treatment under visible light irradiation

      • Junjie Shena
      • Roman Steinbacha
      • John Tobina
      • Mayumi Mouro Nakataa
      • Matthew Bowerb
      • Martin McCoustraa
      • Helen Bridlea
      • Valeria Arrighia
      • Filipe Vilelaa
      • a School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS, United Kingdom
      • b Drinking Water Quality Regulator for Scotland, Edinburgh, EH6 6WW, United Kingdom

      A photoactive benzothiadiazole (BT) based monomer was developed and used in the synthesis of typical polyamide (PA) polymers. The monomer was incorporated in different percentages within the PA backbone of the polymers and their photosensitising ability was tested in different media and conditions. Photochemical experiments in a commercial flow reactor under aerobic conditions showed that the polymers had increased efficiency in singlet oxygen generation compared to the original photoactive monomer. When suspended in aqueous solutions, these materials demonstrated superior photostability towards long-term exposure to light and chemical stability in a wide-range of pH environments. The photoactive polymers were highly capable of degrading two well-known wastewater contaminants, bisphenol A (BPA) and cimetidine, as well as inactivating the waterborne parasite Cryptosporidium. Given the simplicity of the synthetic preparation of the polymers, the absence of metals and their photoactivity under visible light, herein we show that these materials are very promising for simultaneous decontamination and disinfection of water.

       

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      Biodiesel synthesis using integrated acid and base catalysis in continuous flow

      • Mousa Asadi
      • Joel F. Hooper
      • David W. Lupton
      • School of Chemistry, Monash University, Clayton 3800, Victoria, Australia

      The use of biodiesel derived from oils and fats is making an increased contribution as a renewable energy sources. The synthesis of biodiesel involves transesterification of triglycerides to the monoalkyl esters, a process often made challenging by the presence of free fatty acids (FFA). Herein an integrated flow system for the synthesis of biodiesel, employing a solid supported acid catalyst for esterification of FFAs, followed by transesterification using polymer supported N-heterocycle carbene (NHC) catalyst is reported. This system delivers biodiesel in high yields from a variety of fat and oils, using robust and recyclable catalysts.

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      Fine chemical syntheses under flow using SiliaCat catalysts

      • Rosaria Ciriminna a
      • Valerica Pandarus b
      • François Béland *b
      • Mario Pagliaro *a
      • * Corresponding authors a Istituto per lo Studio dei Materiali Nanostrutturati, CNR, via U. La Malfa 153, 90146 Palermo, Italy
      • b SiliCycle, 2500, Parc-Technologique Blvd, Québec, G1P 4S6 Canada

      After reviewing selected recent applications from diverse laboratories, we show how mesoporous organosilica-entrapped catalysts of the SiliaCat series have been successfully used for clean manufacturing of APIs in a number of different reactions carried out under laminar flow in microreactors. The advantages and disadvantages linked to these catalysts in terms of technical and economical sustainability are highlighted. Insight into the scale-up of this technique and related catalytic technologies from the lab scale to industrial production concludes the study.

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      Continuous-flow synthesis of 2H-azirines and their diastereoselective transformation to aziridines

      Marcus Baumann *, Ian R. Baxendale

      • Department of Chemistry, University of Durham, South Road, Durham, DH1 3LE, UK

      Using continuous-flow techniques, a small collection of 2H-azirines was prepared from oxime precursors via mesylation and base-promoted cyclisation. The 2H-azirines were either isolated after in-line purification or derivatised into a selection of 2-substituted aziridines through a telescoped reaction sequence involving nitrile, trifluoromethyl, or hydride nucleophilic addition. Importantly, these 2-substituted aziridines were produced with high cis diastereoselectivity providing access to small chiral heterocyclic entities that hold promise for medicinal chemistry programs because of their druglike features.

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      Continuous flow magnesiation or zincation of acrylonitriles, acrylates, and nitroolefins. Application to the synthesis of butenolides

      • Maximilian A. Ganiek
      • Matthias R. Becker
      • Marthe Ketels
      • Paul Knochel *
      • Department of Chemistry, Ludwig-Maximilians-Universität, Butenandtstr. 5-13, 81377 Munich, Germany

      Scalable continuous flow procedures are reported for the metalation and downstream functionalization of β-substituted acrylates. The flow conditions allow the metalation of acrylonitriles, acrylates, and nitroolefins at 0.25–2.50 mmol/min conversion rates. Magnesiations can be performed with short residence times (1–20 min) and near-ambient temperature using TMPMgCl·LiCl. Further, high temperature zincation (≤90 °C) using TMPZnCl·LiCl is possible. This method allows a simple entry to 2(5H)-furanones by flow generation of magnesiated acrylates and a subsequent reaction with aldehydes.

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      Continuous flow photo-initiated RAFT polymerisation using a tubular photochemical reactor

      • James Gardiner a
      • Christian H. Hornung a
      • John Tsanaktsidis a
      • Duncan Guthrie b
      • a CSIRO Manufacturing, Bag 10, Clayton South, Victoria 3169, Australia
      • b Vapourtec Ltd, Park Farm Business Centre, Bury St Edmunds IP28 6TS, United Kingdom

      The RAFT (Reversible Addition–Fragmentation Chain Transfer) approach allows for greatly enhanced control over radical polymerisation processes, resulting in polymers with low dispersity. Classically, RAFT polymerisations are conducted in batch using thermal initiators. Herein, we describe a novel photo-initiated RAFT polymerisation procedure, using a tubular continuous flow reactor for the polymerisation of (meth)acrylates and acrylamides at close to ambient temperatures. This approach makes use of the excellent light penetration properties of millimetre-size fluoropolymer tubing, enabling the synthesis of multigrams/kgs of RAFT polymer per day. A tubular photochemical reactor presents a very practical and compact design for the continuous manufacture of RAFT polymers in quantities that would otherwise be difficult to achieve in a batch system using photo-initiation.

       

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      Continuous-flow photochemistry: a need for chemical engineering

      • Karine Loubière a,b
      • Michael Oelgemöller c
      • Tristan Aillet a,b
      • Odile Dechy-Cabaret a,d
      • Laurent Prat a,b
      • a CNRS, Laboratoire de Génie Chimique (LGC UMR 5503), 4 allée Emile Monso, BP 84234, 31432 Toulouse, France
      • b Université de Toulouse, INPT, ENSIACET, F-31432 Toulouse, France
      • c James Cook University, College of Science, Technology and Engineering, Townsville, Queensland 4811, Australia
      • d CNRS, Laboratoire de Chimie de Coordination (LCC UPR 8241), 205 route de Narbonne, BP 44099, F-31077 Toulouse, France

      The present paper aims to illustrate that chemical engineering enables to address some of the current challenges and issues in continuous-flow photochemistry. For that, some common limitations encountered in industrial photochemistry are firstly highlighted and a general overview on flow photochemistry equipment is presented. The main challenges linked to photochemical (micro)reactor engineering are subsequently stated. By considering only the case of a purely direct photochemical reactions View the MathML sourceA→Bhυ in homogenous medium, the key factors to consider when implementing such photochemical reactions in microstructured technologies are outlined. Their influence on the outputs (conversion, productivity, photonic efficiency) of this simple type of photochemical reaction is then discussed. The significance of chemical engineering frameworks is finally demonstrated using several examples concerning the understanding of the coupling between the different phenomena involved, the predictions of the performances obtained, the acquisition of kinetics data and the elaboration of strategies for photochemical process intensification and smart scale-up. In the future, the challenge will be to integrate the complexity of photochemistry (e.g. heterogeneous phase reactions) into the present modelling tools so as to enlarge the spectrum of strategies devoted to photochemical process intensification.

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      Efficient metal-free photochemical borylation of aryl halides under batch and continuous-flow conditions†

      Kai Chen, Shuai Zhang, Pei He, Pengfei Li *

      • Center for Organic Chemistry, Frontier Institute of Science and Technology (FIST), Xi'an Jiaotong University, 99 Yanxiang Road, Xi'an, Shaanxi 710054, China

      A rapid, chemoselective and metal-free C–B bond-forming reaction of aryl iodides and bromides in aqueous solution at low temperatures was discovered. This reaction is amenable to batch and continuous-flow conditions and shows exceptional functional group tolerance and broad substrate scope regarding both the aryl halide and the borylating reagent. Initial mechanistic experiments indicated a photolytically generated aryl radical as the key intermediate.

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      Continuous flow photochemistry as an enabling synthetic technology: synthesis of substituted-6(5H)-phenanthridinones for use as poly(ADP-ribose) polymerase inhibitors

      • Y. Fang a
      • G. K. Tranmer *a,b
      • * Corresponding authors a College of Pharmacy, Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
      • b Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, Canada

      Methods utilizing continuous flow photochemistry, an enabling synthetic technology, have been developed for the generation of phenanthridinones via an intramolecular photochemical cyclization of 2-chlorobenzamides for the purposes of generating poly(ADP-ribose) polymerase inhibitors. Herein we report 16 examples of a single-step flow photocyclization which produces substituted phenanthridinones in yields up to 99%, while a two-step method leads directly to phenanthridinones from 2-chlorobenzoyl chlorides and anilines via a novel continuous flow amidation/photocyclization protocol. Overall, the flow photocyclization reactions typically progress in good to excellent yields, and in a superior fashion to analogous batch methods, greatly enabling the drug discovery process.

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      Controlled generation and use of CO in flow†‡

      Steffen V. F. Hansen a,b, Zoe E. Wilson a, Trond Ulven *b, Steven V. Ley *a

      • a Department of Chemistry, University of Cambridge Lensfield Road, Cambridge, CB2 1EW, UK
      • b Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark

      A method for the generation and use of carbon monoxide in flow chemistry has been developed. By using a tube-in-tube reactor, oxalyl chloride can be conveniently and safely hydrolyzed using a NaOH solution to generate CO in the outer stream, which then passes through AF-2400 semi-permeable inner tubing to enrich a reaction stream where it is consumed. The tube-in-tube reactor allows the generation of CO under conditions which would otherwise be incompatible with the reaction conditions. In this way carbonylations can be successfully performed in flow without the use of pressurized gas cylinders. Both alkoxy- and aminocarbonylation was carried out in flow, including a 320 minute continuous run, as proof of concept.

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      The solid copper-mediated C-N cross-coupling of phenylboronic acids under continuous flow conditions

      • Jennifer Bao a
      • Geoffrey K. Tranmer a,b
      • a College of Pharmacy, Faculty of Health Science, University of Manitoba, Winnipeg, MB R3E 0T5, Canada
      • b Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada

      We have developed two general methods for the C–N cross-coupling of phenylboronic acids with amines using solid copper flow reactors, in combination with an oxidant. We have developed one method for a C–N arylation reaction which employs a solid copper coil reactor, in combination with tert-butyl peroxybenzoate, to give products in moderate isolated yields. We have also developed a general method for the C–N cross coupling of phenylboronic acids using a column packed with solid copper powder, in combination with acetic acid and TEMPO, to give products in isolated yields in excess of 75+%. We have also applied our general copper powder method to generate a library of products which highlights the utility of solid copper flow reactors for C–N cross coupling reactions, generating 16 examples in good yields. Mechanistic implications and future directions are also discussed.

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      Visible-light photoredox catalysis using a macromolecular ruthenium complex: reactivity and recovery by size-exclusion nanofiltration in continuous flow†

      Javier Guerra ab, David Cantillo a, C. Oliver Kappe *a, Antonio Macchiarulo a, Antimo Gioiello *a

      • a Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, A-8010 Graz, Austria
      • b Crystal Pharma, Gadea Pharmaceutical Group, a division of AMRI, Parque Tecnológico de Boecillo, Valladolid, 47151, Spain

      A novel macromolecular photoredox catalyst based on [Ru(bpy)3]2+ anchored to a 2nd-generation PAMAM dendrimer has been developed. Its catalytic activity under visible light irradiation and recyclability using organic solvent nanofiltration with a size-exclusion membrane have been explored under continuous flow conditions.

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      Integrating multicomponent flow synthesis and computational approaches for the generation of a tetrahydroquinoline compound based library

      • Bruno Cerra a
      • Serena Mostarda a
      • Chiara Custodi a
      • Antonio Macchiarulo a
      • Antimo Gioiello *a
      • * Corresponding authors
      • a Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, I-06122 Perugia, Italy

      The combination of flow chemistry and computational tools has been successfully applied to prepare a focused library of tricyclic tetrahydroquinolines endowed with drug-like properties. The study illustrates the efficient synthesis of this class of compounds using flow mesoreactors in a multicomponent fashion, as well as the profitable employment of computational chemistry for library diversity analysis. Early biological characterization of selected compounds of the library are also presented for the discovery of novel chemical probes to unravel estrogen receptor signaling pathways.

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      The expanding utility of continuous flow hydrogenation

      • Peter J. Cossar a
      • Lacey Hizartzidis a
      • Michela I. Simone a
      • Adam McCluskey *a
      • Christopher P. Gordon *b
      • * Corresponding authors
      • a Centre for Chemical Biology, Chemistry Building, School of Environmental and Life Science, The University of Newcastle, University Drive, Callaghan, Australia
      • b Nanoscale Organisation and Dynamics Group, School of Science and Health, University of Western Sydney, Locked Bag, Penrith, Australia

      There has been an increasing body of evidence that flow hydrogenation enhances reduction outcomes across a wide range of synthetic transformations. Moreover flow reactors enhance laboratory safety with pyrophoric catalysts contained in sealed cartridges and hydrogen generated in situ from water. This mini-review focuses on recent applications of flow chemistry to mediate nitro, imine, nitrile, amide, azide, and azo reductions. Methodologies to effect de-aromatisation, hydrodehalogenation, in addition to olefin, alkyne, carbonyl, and benzyl reductions are also examined. Further, protocols to effect chemoselective reductions and enantioselective reductions are highlighted. Together these applications demonstrate the numerous advantages of performing hydrogenation under flow conditions which include enhanced reaction throughput, yields, simplified workup, and the potential applicability to multistep and cascade synthetic protocols.

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      Highly efficient and safe procedure for the synthesis of aryl 1,2,3-triazoles from aromatic amine in a continuous flow reactor

      • Federica Stazi a
      • Damiano Cancogni a
      • Lucilla Turco b
      • Pieter Westerduin a
      • Sergio Bacchi a
      • a GlaxoSmithKline Spa, Chemical Development Department, Synthetic Chemistry, Via Fleming 4, 37135 Verona, Italy
      • b GlaxoSmithKline Spa, Analytical Chemistry, Via Fleming 4, 37135 Verona, Italy

      The Letter reports a safe and reliable synthesis of aryl 1,2,3-triazoles from the corresponding anilines via intermediate aryl azides, using a continuous process. The method was applied to a variety of substrates with good to excellent yields, without the need to isolate the reactive and possibly unstable intermediates which were constantly kept at low concentration in the matrix environment.

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      Studies of a Diastereoselective Electrophilic Fluorination Reaction Employing a Cryo-Flow Reactor

      Keiji Nakayama,a, Duncan L. Browne,b, Ian R. Baxendale,b,1, Steven V. Ley,*a

      • a Process Technology Research Laboratories, Pharmaceutical Technology Division, Daiichi Sankyo, Shinomiya, Hiratsuka, Kanagawa, 254-0014, Japan
      • b Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK

      The application of meso-scale flow chemistry in research laboratories continues to increase. Here, we report on the use of a modular cryo-flow device as applied to a diastereoselective fluorination process. The reactor can be incorporated into existing flow chemistry setups to permit continuous processing at low temperatures without recourse to cryogenic consumables.

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      The Changing Face of Organic Synthesis

      Ley, Steven V., Baxendale, Ian R.

      • CHIMIA International Journal for Chemistry, Volume 62, Number 3, March 2008, pp. 162-168(7)

      The article describes the content of the Paul Karrer Lecture given at the University of Zürich on the 20th of June 2007 by Professor Steven V. Ley. The lecture illustrates the work underway within the Chemistry Department at Cambridge to develop microreactors for flow chemistry applications. These modular, small footprint devices are capable of preparing a wide range of compounds including natural products in up to seven synthesis steps.

      Products can generally be obtained in high yield and purity without conventional work-up methods using a variety of reaction mixer chips and pre-packed flow tubes of immobilised reagents and scavengers.

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      Continuous Heterogeneously Catalyzed Oxidation of Benzyl Alcohol in a Ceramic Membrane Packed- Bed Reactor

      • Achilleas Constantinou†¶
      • Gaowei Wu
      • Albert Corredera
      • Peter Ellis
      • Donald Bethell§
      • Graham J. Hutchings
      • Simon Kuhn
      • Asterios Gavriilidis*†
      • Department of Chemical Engineering, University College London, Torrington Place, London, WC1E 7JE, United Kingdom
      • Division of Chemical and Petroleum Engineering, School of Engineering, London South Bank University, London, SE1 0AA, United Kingdom
      • Johnson Matthey, Blounts Court Road, Reading, RG4 9NH, United Kingdom
      • § Department of Chemistry, University of Liverpool, Crown Street, Liverpool L69 7ZD, United Kingdom
      • School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, United Kingdom
      • Department of Chemical Engineering, KU Leuven, W. de Croylaan 46, 3001 Leuven, Belgium
      Continuous Heterogeneously Catalyzed Oxidation of Benzyl Alcohol in a Ceramic Membrane Packed- Bed Reactor

      A ceramic membrane reactor was investigated for the continuous catalytic oxidation of benzyl alcohol with oxygen. The reactor had a concentric configuration. An inner tube created an annulus for the catalyst packed-bed (0.9 wt % Au–Pd/TiO2, particle size 90–125 μm) through which the liquid phase (benzyl alcohol, neat or dissolved in o-xylene) flowed. This was followed by the tubular ceramic membrane, which consisted of layers of alumina and a zirconia top layer with a nominal average pore size of 50 nm. The role of the membrane was to provide an interface for gas and liquid to come in contact. Pure oxygen was fed to the opposite side of the membrane in the outer shell of the reactor. Temperature affected conversion but not selectivity, possibly because of insufficient supply of oxygen. However, increasing catalyst contact time or decreasing benzyl alcohol concentration improved selectivity and conversion, indicating that a key parameter was the balance between oxygen supply by the membrane vs oxygen demand by the reaction. By adjusting the operating parameters, reaction performance improved. Selectivity to benzaldehyde 88% and conversion of benzyl alcohol 75% were obtained at 3.2 bara of gas pressure, 24444 gcat·s/galcohol catalyst contact time, 0.5 M benzyl alcohol concentration, and temperature of 120 °C. This performance was comparable to simulated trickle bed operation, where oxygen and substrate were premixed before entering the catalyst packed bed. The membrane reactor offers safer operation, since flammable oxygen/organic mixtures formed in the trickle bed are avoided.

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      Continuous flow Buchwald–Hartwig amination of a pharmaceutical intermediate†

      Polina Yaseneva a, Paul Hodgson a, Jacek Zakrzewski a, Sebastian Falß b, Rebecca E. Meadows c, Alexei A. Lapkin * a

      •   a Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK. E-mail: aal35@cam.ac.uk Fax: +44 (0)1223 334796
      • INVITE GmbH, Chempark Leverkusen, 51373 Leverkusen, Germany
      • Pharmaceutical Development, AstraZeneca, Silk Road Business Park, Macclesfield SK10 2NA, UK

      A flow process for direct amination of a pharmaceutically relevant substrate using a Pd-NHC based catalyst was demonstrated in a lab-scale mini-plant and in a pilot-scale plant. The lab-scale mini-plant was used to determine catalyst stability under recycling conditions. Results in the mini-plant have shown the maximum space–time yield between the three types of reactor systems: a batch reactor, a mini-plant and a pilot plant. A comprehensive life-cycle assessment study of the synthesis of organometallic catalysts and their impact on the overall LCA of flow vs. batch syntheses was developed. Combined with a simplified economic analysis, the LCA study confirmed the benefits of switching to flow.

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      Thermolysis of 1,3-dioxin-4-ones: fast generation of kinetic data using in-line analysis under flow

      • Thomas Duranda
      • Cyril Henrya
      • David Boliena
      • David C. Harrowvena
      • Sally Bloodwortha
      • Xavier Franckb
      • Richard J. Whitby* a
      • a Chemistry, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, UK
      • b Normandie Université, COBRA, UMR 6014 & FR 3038, Université de Rouen, INSA Rouen, CNRS, 1 rue Tesnière, 76821 Mont-Saint-Aignan Cedex, France
      Thermolysis of 1,3-dioxin-4-ones: fast generation of kinetic data using in-line analysis under flow

      Rapid acquisition of kinetic data is demonstrated with a commercial meso-scale flow reactor, using a step-change in flow rate or ‘push-out’ from the flow line. For thermolysis of 1,3-dioxin-4-ones (1), we obtain excellent reproducibility in the activation energies measured from spectroscopic data collected by in-line UV or transmission FT-IR monitoring of the output during the transitional period between two flow rates (±3 kJ mol−1, 0.7 kcal mol−1). Analysis of multi-component UV and IR data is conducted using an orthogonal projection approach (multivariate curve resolution by alternating least squares) for complex spectra, or by calibration-less integration of non-overlapping peak absorbance. All analysis methods were validated using off-line 1H NMR analysis, and kinetic parameters obtained using the method of a flow rate step-change were validated against conventional steady-state measurements in which time-series data were acquired across multiple experiments. Thermal transfer and dispersion effects are addressed. The experimental methods described herein are valuable for accelerated reaction study and in process development.

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      Continuous photochemistry: the flow synthesis of ibuprofen via a photo-Favorskii rearrangement

      • M. Baumanna
      • Ian R. Baxendale* a
      • a Department of Chemistry, University of Durham, South Road, Durham, UK
      The flow synthesis of ibuprofen via a photo-Favorskii rearrangement

      A new enabling technology for performing photochemical reactions in a continuous fashion is presented. This photo-reactor is compatible with existing flow systems and can be furthermore linked to a photo-spectrometer in order to allow for real time analysis of photochemical reactions. In this communication we wish to report the profiling of this system and its application to the continuous synthesis of ibuprofen based on a photo-Favorskii rearrangement reaction of a readily available α-chloropropiophenone precursor.

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      Automated glycan assembly of xyloglucan oligosaccharides

      • Pietro Dallabernardinaa b
      • Frank Schuhmachera b
      • Peter H. Seebergera b
      • Fabian Pfrengle* a b
      • a Department of Biomolecular Systems, Max-Planck-Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany
      • b Freie Universität Berlin, Institute of Chemistry and Biochemistry, Arnimallee 22, 14195 Berlin, Germany
      Automated glycan assembly of xyloglucan oligosaccharides

      We report the automated glycan assembly of oligosaccharide fragments related to the hemicellulose xyloglucan (XG). Iterative addition of monosaccharide and disaccharide building blocks to a solid support provided seven cellulose and xyloglucan fragments including XXGG- and XXXG-type oligosaccharides.

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      Dynamic flow synthesis of porous organic cages

      • Michael E. Briggsa
      • Anna G. Slatera
      • Neil Lunta
      • Shan Jianga
      • Marc A. Littlea
      • Rebecca L. Greenawaya
      • Tom Hasella
      • Claudio Battilocchiob
      • Steven V. Leyb
      • Andrew I. Cooper* a
      • a Department of Chemistry and Centre for Materials Discovery, University of Liverpool, Crown Street, Liverpool, UK
      • b Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK
      Dynamic flow synthesis of porous organic cages

      The dynamic covalent synthesis of two imine-based porous organic cages was successfully transferred from batch to continuous flow. The same flow reactor was then used to scramble the constituents of these two cages in differing ratios to form cage mixtures. Preparative HPLC purification of one of these mixtures allowed rapid access to a desymmetrised cage molecule.

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      An integrated flow and microwave approach to a broad spectrum protein kinase inhibitor

      • Cecilia Russella
      • Andrew J. S. Lina
      • Peter Hainsb
      • Michela I. Simonea
      • Phillip J. Robinsonb
      • Adam McCluskey* a
      • A Centre for Chemical Biology, Chemistry, School of Environmental and Life Science, The University of Newcastle, University Drive, Callaghan, Australia
      • B Children's Medical Research Institute, 214 Hawkesbury Road, Westmead, Australia
      An integrated flow and microwave approach to a broad spectrum protein kinase inhibitor

      The protein kinase inhibitor CTx-0152960 (6, 2-((5-chloro-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide), and the piperazinyl analogue, CTx-0294885 (7, 2-((5-chloro-2-((4-piperazin-1-ylphenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide), were prepared using a hybrid flow and microwave approach. The use of flow chemistry approaches avoided the need for Boc-protection of piperidine in the key SNAr coupling with 1-fluoro-4-nitrobenzene. Microwave coupling of 4-morphilinoaniline 8 and 4-(piperazine-1-yl)aniline 9 with 2-(2,5-dichloropyrimidine-4-ylamino)-N-methylbenzamide 10, proved to be the most efficacious route to the target analogues 6 and 7. This hybrid methodology reduced the number of synthetic steps, gave enhanced overall yields and increased atom economy through step reduction and minimal requirement for chromatographic purification, relative to the original batch synthesis approach.

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      A Flow-based Synthesis of Telmisartan

      Alex Martin, Ali Siamaki, Katherine Belecki, B. Gupton

      • Department of Chemistry and Department of Chemical and Life Science Engineering Virginia Commonwealth University 601 W. Main St. Richmond Virginia 23284 United States

      A highly efficient continuous synthesis has been developed for telmisartan, the active ingredient in the antihypertensive drug, Micardis. This synthetic route employs a convergent strategy that requires no intermediate purifications or solvent exchanges. The key step in the reaction scheme is a Suzuki cross-coupling reaction between two functionalized benzimidazoles that is catalyzed by a solid-supported Pd catalyst. This flow-based approach utilizes a tubular reactor system coupled with a plug flow packed bed cartridge unit that produces telmisartan in an 81% isolated yield.

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      The Preparation of Ethyl Levulinate Facilitated by Flow Processing: The Catalyzed and Uncatalyzed Esterification of Levulinic Acid

      Meghan P. Negus1, Andrew C. Mansfield2, Nicholas E. Leadbeater1

      • 1 Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, CT 06269, United States
      • 2 Vapourtec Ltd., Park Farm Business Centre, Bury St. Edmunds IP28 6TS, United Kingdom
      • 3 Department of Community Medicine and Health Care, University of Connecticut Health Center, The Exchange, 263 Farmington Ave, Farmington, CT 06030, United States

      The catalyzed and uncatalyzed preparation of ethyl levulinate from levulinic acid and ethanol is presented. In the case of acid-catalyzed reactions, conditions were optimized in batch using microwave heating and then scaled-up using continuousflow processing. Both p-toluenesulfonic acid and sulfuric acid were used as catalysts, the latter proving most amenable. For the uncatalyzed reactions, all reactions were performed under continuous-flow conditions, using apparatus capable of operating at high temperature and pressure. Optimal conditions for the uncatalyzed process required heating a 3.6-M solution of levulinic acid in ethanol at 270 °C with a residence time of 30 min.

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      Photodecarboxylations in an advanced meso-scale continuous flow photoreactor

      Sam Josland1, Saira Mumtaz2, Michael Oelgemöller2 *

      • 1 University of Southampton, Department of Chemistry, University Road, Southampton, SO17 1BJ, United Kingdom
      • 2 James Cook University, College of Science, Technology and Engineering, Townsville, QLD 4811, Australia

      Selected photodecarboxylations of phthalimides were realized under continuous-flow conditions using an advanced meso-scale photoreactor. The improved efficiency, yields, and productivities of these photochemical reactions highlight the benefits of using flow as opposed to conventional batch operation modes. Flow chemistry furthermore allows for an easy combination of multiple reaction steps in series. This is demonstrated by the successful synthesis of a pharmaceutical target molecule through a tandem photochemical-thermal procedure carried out in uninterrupted flow.

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      Efficient Continuous-Flow Synthesis of Macrocyclic Triazoles

      Anne-Catherine Bédard, Jeffrey Santandrea, Shawn K. Collins

      • Department of Chemistry and Centre for Green Chemistry and Catalysis, University of Montreal

      The continuous-flow synthesis of a series of 11- to 26-membered macrocycles via copper-catalyzed azide-alkyne cycloaddition is reported. The approach employs homogeneous catalysis to promote formation of triazole-containing macrocycles in good to excellent yields (65–90%) at relatively high concentration (30–50 mM) using a phase separation strategy.

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      Amination of Aryl Halides and Esters Using Intensified Continuous Flow Processing

      Thomas M. Kohl *, Christian H. Hornung, John Tsanaktsidis

      • CSIRO Manufacturing Flagship, Bag 10, Clayton South, Victoria 3169, Australia

      Significant process intensification of the amination reactions of aryl halides and esters has been demonstrated using continuous flow processing. Using this technology traditionally difficult amination reactions have been performed safely at elevated temperatures. These reactions were successfully conducted on laboratory scale coil reactor modules with 1 mm internal diameter (ID) and on a preparatory scale tubular reactor with 6 mm ID containing static mixers.

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      A Short Multi-step Flow Synthesis of a Potential Spirocyclic Fragrance Component

      Ian R. Baxendale*

      • Department of Chemistry, University of Durham, South Road, Durham, DH1 3LE, UK

      The search for novel chemical architectures displaying improved biological properties is a never-ending synthetic challenge. In this context many new test structures are often conceived by selecting and replicating specific design elements from naturally occurring molecules and displaying them in an alternative format by way of a new chemical assembly. Constructing these newly designed compounds can be a timely and expensive process especially when a large quantity of the target material is required for physiochemical and property testing. To permit easier scale-up and safer working practice, many chemical researchers are employing flow chemistry approaches to aid in their synthesis challenges. The preparation of a key spirocyclic lactone using flow-based reaction processing techniques is reported.

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      Flow Synthesis of 2-Methylpyridines via α-Methylation

      Camille Manansala1, Geoffrey K. Tranmer1 2 *

      • 1 College of Pharmacy, Faculty of Health Science, University of Manitoba, Winnipeg, MB R3E 0T6, Canada
      • 2 Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada

      A series of simple 2-methylpyridines were synthesized in an expedited and convenient manner using a simplified bench-top continuous flow setup. The reactions proceeded with a high degree of selectivity, producing α-methylated pyridines in a much greener fashion than is possible using conventional batch reaction protocols. Eight 2-methylated pyridines were produced by progressing starting material through a column packed with Raney® nickel using a low boiling point alcohol (1-propanol) at high temperature. Simple collection and removal of the solvent gave products in very good yields that were suitable for further use without additional work-up or purification. Overall, this continuous flow method represents a synthetically useful protocol that is superior to batch processes in terms of shorter reaction times, increased safety, avoidance of work-up procedures, and reduced waste. A brief discussion of the possible mechanism(s) of the reaction is also presented which involves heterogeneous catalysis and/or a Ladenberg rearrangement, with the proposed methyl source as C1 of the primary alcohol.

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      The development of a short route to the API ropinirole hydrochloride

      • Zeshan Yousufa
      • Andrew K. Richardsb
      • Andrew N. Dwyerc
      • Bruno Linclaua
      • David C. Harrowven* a
      • a Chemistry, University of Southampton, Highfield, Southampton, UK
      • b GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, UK
      • c Formally at GlaxoSmithKline Innovation and Sustainable Manufacturing COE, Worthing, UK
      The development of a short route to the API ropinirole hydrochloride

      A four-step, three-stage synthesis of the API ropinirole hydrochloride has been developed from a commercially available naphthalene derivative. The new route has half the step-count and twice the overall yield of the current manufacturing process. Key features of the synthesis are a regioselective Birch reduction and an ozonolysis with concomitant ring closure to induce the required ring contraction.

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      Rapid Discovery of a Novel Series of Abl Kinase Inhibitors by Application of an Integrated Microfluidic Synthesis and Screening Platform

      • Bimbisar Desai
      • Karen Dixon
      • Elizabeth Farrant
      • Qixing Feng
      • Karl R. Gibson
      • Willem P. van Hoorn
      • James Mills
      • Trevor Morgan
      • David M. Parry
      • Manoj K. Ramjee
      • Christopher Nicholas Selway
      • Gary J. Tarver
      • Gavin Whitlock
      • Adrian G. Wright
      • Cyclofluidic Ltd.

      Drug discovery faces economic and scientific imperatives to deliver lead molecules rapidly and efficiently. Using traditional paradigms the molecular design, synthesis, and screening loops enforce a significant time delay leading to inefficient use of data in the iterative molecular design process. Here, we report the application of a flow technology platform integrating the key elements of structure–activity relationship (SAR) generation to the discovery of novel Abl kinase inhibitors. The platform utilizes flow chemistry for rapid in-line synthesis, automated purification, and analysis coupled with bioassay. The combination of activity prediction using Random-Forest regression with chemical space sampling algorithms allows the construction of an activity model that refines itself after every iteration of synthesis and biological result. Within just 21 compounds, the automated process identified a novel template and hinge binding motif with pIC50 > 8 against Abl kinase — both wild type and clinically relevant mutants. Integrated microfluidic synthesis and screening coupled with machine learning design have the potential to greatly reduce the time and cost of drug discovery within the hit-to-lead and lead optimization phases.

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      Investigating the continuous synthesis of a nicotinonitrile precursor to nevirapine

      • Ashley R. Longstreet1
      • Suzanne M. Opalka1
      • Brian S. Campbell1
      • B. Frank Gupton2
      • Tyler McQuade1
      • 1 Department of Chemistry and Biochemistry, Florida State University, United States
      • 1 Department of Chemistry, Virginia Commonwealth University, United States

      2-Chloro-3-amino-4-picoline (CAPIC) is a strategic building block for the preparation of nevirapine, a widely-prescribed non-nucleosidic reverse transcriptase inhibitor for the treatment of HIV-infected patients. A continuous synthesis to the bromo derivative of a CAPIC intermediate, 2-bromo-4-methylnicotinonitrile, that terminates in a dead-end crystallization is described. The route uses inexpensive, acyclic commodity-based raw materials and has the potential to enable lower cost production of nevirapine as well as other value added structures that contain complex pyridines. The route terminates in a batch crystallization yielding high purity CAPIC. This outcome is expected to facilitate regulatory implementation of the overall process.

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      Efficient synthesis of panaxadiol derivatives using continuous-flow microreactor and evaluation of anti-tumor activity

      Yan Wua,1, Wei-Qi Chenb,1, Yu-Qing Zhaoc, Hu-Ri Piaoa

      • aKey Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, Yanbian University College of Pharmacy, China
      • bDepartment of Chemistry, Fudan University, Shanghai, China
      • cSchool of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
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      Continuous Reductions and Reductive Aminations Using Solid Sodium borohydride

      • Kerry Gilmore
      • Stella Vukelic
      • D. Tyler McQuade†§
      • Beate Koksch
      • Peter H. Seeberger*†‡
      • Max Planck Institute of Colloids and Interfaces, Germany
      • Institute of Chemistry and Biochemistry, Freie Universität Berlin, Germany
      • § Department of Chemistry and Biochemistry, Florida State University, United States

      Most successful reactions carried out under continuous flow conditions mix homogeneous solutions yielding homogeneous products. Using solids is avoided to prevent pump and reactor clogging; even though solid reagents may often be the best choice for a given transformation. Here we demonstrate that by pumping aldehydes, ketones, or in situ formed imines through a specially formulated NaBH4 column results in efficient reductions. The column design and performance characteristics, along with substrate scope, are discussed.

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      Photodecarboxylative Benzylations of N-Methoxyphthalimide under Batch and Continuous-Flow Conditions

      • Hossein Mohammadkhani Pordanjani A B
      • Christian Faderl A C
      • Jun Wang A
      • Cherie A. Motti D
      • Peter C. Junk A
      • Michael Oelgemöller A E
      • A James Cook University, College of Science, Technology and Engineering, Townsville, Qld 4811, Australia.
      • B Faculty of Chemistry, Bu-Ali Sina University, Hamedan, 6517838683, Iran.
      • C Institut für Organische Chemie, Universität Regensburg, Universitätsstr. 31, D-93053 Regensburg, Germany.
      • D Australian Institute of Marine Science (AIMS), Biomolecular Analysis Facility, Townsville, Qld 4810, Australia.
      • E Corresponding author. Email: michael.oelgemoeller@jcu.edu.au
      Photodecarboxylative Benzylations of N-Methoxyphthalimide under Batch and Continuous-Flow Conditions

      A series of photodecarboxylative benzylations of N-methoxyphthalimide were successfully realised using easily accessible starting materials. The reactions proceeded smoothly and the corresponding benzylated hydroxyphthalimidines were obtained in moderate to good yields of 52–73 %. No competing photoinduced dealkoxylation of the N-methoxy group was observed. The reaction with potassium phenylacetate was subsequently investigated in an advanced continuous-flow photoreactor. The reactor allowed rapid optimization of the reaction conditions and gave the desired benzylated product in higher yield and shorter irradiation time compared with the batch process.

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      Chemical Assembly Systems: Layered Control for Divergent, Continuous, Multistep Syntheses of Active Pharmaceutical Ingredients

      Dr. Diego Ghislieri, Dr. Kerry Gilmore, Prof. Dr. Peter H. Seeberger*

      • Department of Biomolecular Systems, Max-Planck Institute for Colloids and Interfaces, Universität Berlin, Germany

      While continuous chemical processes have attracted both academic and industrial interest, virtually all active pharmaceutical ingredients (APIs) are still produced by using multiple distinct batch processes. To date, methods for the divergent multistep continuous production of customizable small molecules are not available. A chemical assembly system was developed, in which flow-reaction modules are linked together in an interchangeable fashion to give access to a wide breadth of chemical space. Control at three different levels—choice of starting material, reagent, or order of reaction modules—enables the synthesis of five APIs that represent three different structural classes (γ-amino acids, γ-lactams, β-amino acids), including the blockbuster drugs Lyrica and Gabapentin, in good overall yields (49–75 %).

      We gratefully acknowledge financial support from the Max-Planck Society. We thank Dr. D. Kopetzki for helpful discussions, Dr. M. Rasparini from providing a pure sample of Pregabalin and Thales Nano for providing the H-Cube hydrogenator.

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      Light-Induced C-H Arylation of (Hetero)arenes by In Situ Generated Diazo Anhydrides

      Dr. David Cantillo1, Dr. Carlos Mateos2, Dr. Juan A. Rincon2, Dr. Oscar de Frutos2 *, Prof. Dr. C. Oliver Kappe1 *

      • 1 Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz (Austria)
      • 2 Centro de Investigación Lilly S. A. Avda. de la Industria 30, 28108 Alcobendas-Madrid (Spain)

      Diazo anhydrides (Ar-N=N-O-N=N-Ar) have been known since 1896 but have rarely been used in synthesis. This communication describes the development of a photochemical catalyst-free C-H arylation methodology for the preparation of bi(hetero)aryls by the one-pot reaction of anilines with tert-butyl nitrite and (hetero)arenes under neutral conditions. The key step in this procedure is the in situ formation and subsequent photochemical (>300 nm) homolytic cleavage of a transient diazo anhydride intermediate. The generated aryl radical then efficiently reacts with a (hetero)arene to form the desired bi(hetero)aryls producing only nitrogen, water, and tert-butanol as byproducts. The scope of the reaction for several substituted anilines and (hetero)arenes was investigated. A continuous-flow protocol increasing selectivity and safety has been developed enabling the experimentally straightforward preparation of a variety of substituted bi(hetero)aryls within 45 min of reaction time.

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      Two-Stage Flow Synthesis of Coumarin via O-Acetylation of Salicylaldehyde

      Xin Li1, Anbang Chen1, Yangzhi Zhou1, Lingling Huang2, Zheng Fang2, Haifeng Gan1, Kai Guo1

      • 1 College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, 30 Puzhu Rd S., Nanjing 211816, PR China
      • 2 School of Pharmaceutical Sciences, Nanjing Tech University, 30 Puzhu Rd S., Nanjing 211816, PR China
      • 3 State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, 30 Puzhu Rd S., Nanjing 211816, PR China

      Continuous-flow synthesis of coumarin was realized in a tandem microflow system containing two microreactors in this study. Generally, better reaction yield (91%) and less side reaction were obtained in the flow system compared with conventional method. Interestingly, different reaction pathways were observed between continuous-flow system and batch methods.

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      Flow Alkylation of Thiols, Phenols, and Amines Using a Heterogenous Base in a Packed-Bed Reactor

      Alastair Baker1, Michael Graz2, Robert Saunders2, Gareth J. S. Evans2, Ilaria Pitotti1 Thomas Wirth1

      • 1 School of Chemistry, Cardiff University, Park Place, Main Building, Cardiff CF10 3AT, UK
      • 2 Neem Biotech, Willowbrook Technical Units, Llandogo Road, St. Mellons, Cardiff CF3 0EF, UK

      Rapid alkylations of thiols are performed in a packed-bed flow reactor where potassium carbonate acts as a heterogeneous base in anhydrous solvents at ambient temperature. The reaction also has a high efficiency as the removal of the solvent is the only work up required to isolate the product. The products can be used in a subsequent oxidation which was performed sequentially in semibatch mode. The alkylations of phenol and benzyl amine have been demonstrated on an array of bases, but higher temperatures and longer reaction times are required than with thiols.

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      An efficient continuous flow process for the synthesis of a non-conventional mixture of fructooligosaccharides

      Paolo Zambellia, Lucia Tamborinib, Samuele Cazzamallib, Andrea Pintob, Stefania Ariolia, Silvia Balzarettia, Francisco J. Plouc, Lucia Fernandez-Arrojoc, Francesco Molinaria, Paola Contib, Diego Romanoa

      • a Department of Food Environmental and Nutritional Science (DeFENS), University of Milan, Via Mangiagalli, 20133 Milan, Italy
      • b Department of Pharmaceutical Sciences (DISFARM), University of Milan, Via Mangiagalli 25, 20133 Milan, Italy
      • c Instituto de Catálisis y Petroleoquímica, CSIC, 28049 Madrid, Spain

      A sustainable and scalable process for the production of a new mixture of fructooligosaccharides (FOS) was developed using a continuous-flow approach based on an immobilized whole cells-packed bed reactor. The technological transfer from a classical batch system to an innovative flow environment allowed a significant improvement of the productivity. Moreover, the stability of this production system was ascertained by up to 7 days of continuous working. These results suggest the suitability of the proposed method for a large-scale production of the desired FOS mixture, in view of a foreseeable use as a novel prebiotic preparation.

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      A practical deca-gram scale ring expansion of (R)-(−)-carvone to (R)-(+)-3-methyl-6-isopropenyl- cyclohept-3-enone-1

      • Leandro de C. Alvesa
      • André L. Desideráa
      • Kleber T. de Oliveiraa
      • Sean Newtonb
      • Steven V. Ley* b
      • Timothy J. Brocksom* a
      • a Departamento de Química, Universidade Federal de São Carlos, P.O. Box 676, São Carlos – SP, Brazil
      • b Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK
      A practical deca-gram scale ring expansion of (R)-(−)-carvone to (R)-(+)-3-methyl-6-isopropenyl- cyclohept-3-enone-1

      A route to enantiopure (R)-(+)-3-methyl-6-isopropenyl-cyclohept-3-enone-1, an intermediate for terpenoids, has been developed and includes a highly chemo- and regioselective Tiffeneau–Demjanov reaction. Starting from readily available (R)-(−)-carvone, this robust sequence is available on a deca-gram scale and uses flow chemistry for the initial epoxidation reaction. The stereochemistry of the addition of two nucleophiles to the carbonyl group of (R)-(−)-carvone has been determined by X-ray diffraction studies and chemical correlation.

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      Factors Influencing the Regioselectivity of the Oxidation of Asymmetric Secondary Amines with Singlet Oxygen

      Dr. Dmitry B. Ushakov 1 †, Matthew B. Plutschack 1 †, Dr. Kerry Gilmore 1 *, Prof. Dr. Peter H. Seeberger 1

      • 1 Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam (Germany)

      Aerobic amine oxidation is an attractive and elegant process for the α functionalization of amines. However, there are still several mechanistic uncertainties, particularly the factors governing the regioselectivity of the oxidation of asymmetric secondary amines and the oxidation rates of mixed primary amines. Herein, it is reported that singlet-oxygen-mediated oxidation of 1° and 2° amines is sensitive to the strength of the α-C[BOND]H bond and steric factors. Estimation of the relative bond dissociation energy by natural bond order analysis or by means of one-bond C[BOND]H coupling constants allowed the regioselectivity of secondary amine oxidations to be explained and predicted. In addition, the findings were utilized to synthesize highly regioselective substrates and perform selective amine cross-couplings to produce imines.

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      Electroactive and Photoactive Poly[Isoindigo-alt-EDOT] Synthesized Using Direct (Hetero)Arylation Polymerization in Batch and in Continuous Flow

      • François Grenier
      • Badrou Réda Aïch † ‡
      • Yu-Ying Lai §
      • Maxime Guérette
      • Andrew B. Holmes §
      • Ye Tao
      • Wallace W. H. Wong * §
      • Mario Leclerc * †
      • Département de Chimie, Université Laval, Québec City, Qc G1V 0A6, Canada
      • Information and Communications Technologies Portfolio, National Research Council of Canada, Ottawa, ON K1A 0R6, Canada
      • § School of Chemistry, Bio21 Institute, the University of Melbourne, 30 Flemington Road, Parkville, Victoria 3010, Australia
      Electroactive and Photoactive Poly[Isoindigo-alt-EDOT] Synthesized Using Direct (Hetero)Arylation Polymerization in Batch and in Continuous Flow

      In this work, a combined approach was used to obtain a low-cost material for organic electronics by focusing on inexpensive monomers, short synthetic pathway, high-yielding polymerization method, low waste, and easy scalability. To achieve this, a new material, poly[isoindigo-alt-3,4-ethylenedioxythiophene], was synthesized using direct (hetero)arylation polymerization (DHAP). Only a few synthetic steps are required to obtain this material, and no organometallic intermediates are used. In order to make a bigger step toward a truly inexpensive technology, continuous flow methods were applied for the first time to DHAP. This method helped solving a common problem encountered in conjugated polymers synthesis, namely, batch-to-batch variations. Electronic properties of this polymeric material were evaluated using field effect transistors (μh = 7 × 10–3 cm2·V–1·s–1) and solar cells (η = 3.0%).

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      A Concise Flow Synthesis of Efavirenz†

      Dr. Camille A. Correia1, Dr. Kerry Gilmore1, Prof. Dr. D. Tyler McQuade3, Prof. Dr. Peter H. Seeberger1 2 *

      • 1 Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam (Germany)
      • 2 Institute for Chemistry and Biochemistry, Freie Universität Berlin, Arnimallee 22, 14195 Berlin (Germany)
      • 3 Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306 (USA)

      Efavirenz is an essential medicine for the treatment of HIV, which is still inaccessible to millions of people worldwide. A novel, semi-continuous process provides rac-Efavirenz with an overall yield of 45 %. This streamlined proof-of-principle synthesis relies on the efficient copper-catalyzed formation of an aryl isocyanate and a subsequent intramolecular cyclization to install the carbamate core of Efavirenz in one step. The three-step method represents the shortest synthesis of this life-saving drug to date.

      We gratefully acknowledge generous financial support from the Max-Planck-Society. We also thank Vapourtec for lending us a fully equipped E-Series Flow System.

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      Flow synthesis of ethyl isocyanoacetate enabling the telescoped synthesis of 1,2,4-triazoles and pyrrolo-[1,2-c]pyrimidines

      • Marcus Baumann 1
      • Antonio M. Rodriguez Garcia 1 2
      • Ian R. Baxendale * 1
      • 1 Department of Chemistry, Durham University, South Road, Durham, UK
      • 2 Universidad de Castilla-La Mancha, Departamento de Química Orgánica, Facultad de Ciencias y Tecnologías Químicas, Avd. Camilo José Cela, 10, 13071 Ciudad Real, Spain
      Flow Synthesis and subsequent functionalisation

      The efficient flow synthesis of important heterocyclic building blocks based on the 1,2,4-triazole and pyrrolo[1,2-c]pyrimidine scaffold has been achieved. Crucially, a telescoped continuous flow process was developed based on the reaction of N-formylglycine with triphosgene to deliver a stream of ethyl isocyanoacetate in situ, which subsequently yielded the desired heterocyclic entities in a telescoped reaction. Additionally, the functionalisation of the pyrrolo[1,2-c]pyrimidine core via subsequent SEAr reactions was studied revealing insight into a ‘halogen dance’ phenomenon associated with these medicinally relevant architectures.

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      Development of a flow method for the hydroboration/oxidation of olefins

      • José A. Souto* 1 2
      • Robert A. Stockman3
      • Steven V. Ley1
      • 1 Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
      • 2 Departamento de Química Orgánica, Universidade de Vigo, Vigo, Spain
      • 3 School of Chemistry, University of Nottingham, Nottingham, UK
      Development of a flow method for the hydroboration/oxidation of olefins

      A method for the continuous preparation of alcohols by hydroboration/oxidation of olefins using flow techniques is described. The process allows the isolation of up to 120 mmol h−1 of the desired alcohol in a very rapid manner with good functional group tolerance. The flow setup can be modified to perform a continuous extraction of the desired alcohol from the biphasic mixture produced by the reaction.

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      Making Ends Meet: Flow Synthesis as the Answer to Reproducible High-Performance Conjugated Polymers on the Scale that Roll-to-Roll Processing Demands

      Martin Helgesen, Jon E. Carlé, Gisele A. dos Reis Benatto, Roar R. Søndergaard, Mikkel Jørgensen, Eva Bundgaard, Frederik C. Krebs

      • Department of Energy Conversion and Storage, Technical University of Denmark, Roskilde, Denmark

      Continuous flow methods are employed for the controlled polymerization of the roll-to-roll (R2R) compatible polymer PBDTTTz-4 including optimization and upscaling experiments. The polymerization rate and materials’ quality can be increased significantly with the continuous flow method where reaction times down to 10 min afforded PBDTTTz-4 with high molecular weight and a constant quality. The flow method enables full control of the molecular weight via tuning of the flow speed, catalyst loading, and temperature and avoids variation in materials’ quality associated with conventional batch synthesis. Upscaling from 300 mg batch synthesis to 10 g flow synthesis affords PBDTTTz-4 with a production rate of up to 120 g day−1 for a very simple in-house build flow reactor. An average power conversion efficiency (PCE) of 3.5% is achieved on a small scale (1 cm2) and an average PCE of 3.3% is achieved on a large scale (29 cm2). This shows that small device efficiencies can be scaled when using full R2R processing of flexible and encapsulated carbon-based modules without the use of vacuum, indium-tin-oxide, or silver, with the best achieving a PCE of 3.8% PCE.

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      Reevaluation of the 2-nitrobenzyl protecting group for nitrogen containing compounds: an application of flow photochemistry

      • Chloe I. Wendell, Michael J. Boyd
      • Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA, United States
      2-nitrobenzyl protecting group for nitrogen containing compounds

      Photochemistry under continuous flow conditions has many potential benefits for photochemical reactions that are problematic in batch. The 2-nitrobenzyl moiety is a photolabile protecting group for nitrogen. However, N-deprotection is generally impractical and, therefore, has not been extensively adopted. This Letter reports significant improvements in the N-deprotection of the 2-nitrobenzyl group through the application of continuous flow photolysis. This procedure was applied to a variety of substrates including indoles, indazoles, pyrazoles and secondary amines. Significant improvement in yield, reaction time and scalability was observed under continuous flow conditions.

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      Flow synthesis of organic azides and the multistep synthesis of imines and amines using a new monolithic triphenylphosphine reagent

      • Catherine J. Smith
      • Christopher D. Smith
      • Nikzad Nikbin
      • Steven V. Ley
      • Ian R. Baxendale
      • Innovative Technology Centre, Cambridge, UK

      Here we describe general flow processes for the synthesis of alkyl and aryl azides, and the development of a new monolithic triphenylphosphine reagent, which provides a convenient format for the use of this versatile reagent in flow. The utility of these new tools was demonstrated by their application to a flow Staudinger aza-Wittig reaction sequence. Finally, a multistep aza-Wittig, reduction and purification flow process was designed, allowing access to amine products in an automated fashion.

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      Generation and Trapping of Ketenes in Flow

      Cyril Henry1, David Bolien1, Bogdan Ibanescu1, Sally Bloodworth1, David C. Harrowven1, Xunli Zhang2, Andy Craven3, Helen F. Sneddon3, Richard J. Whitby1 *

      • 1 Chemistry, University of Southampton, Southampton, HANTS, SO17 1BJ, UK,
      • 2 Bioengineering Group, Faculty of Engineering and the Environment, University of Southampton, Southampton, HANTS, SO17 1BJ, UK
      • 3 GlaxoSmithKline R&D Ltd., Medicines Research Centre, Gunnels Wood Road, Stevenage, HERTS, SG1 2NY, UK

      Ketenes were generated by the thermolysis of alkoxyalkynes under flow conditions, and then trapped with amines and alcohols to cleanly give amides and esters. For a 10 min reaction time, temperatures of 180, 160, and 140 °C were required for >95 % conversion of EtO, iPrO, and tBuO alkoxyalkynes, respectively. Variation of the temperature and flow rate with inline monitoring of the output by IR spectroscopy allowed the kinetic parameters for the conversion of 1-ethoxy-1-octyne to be easily estimated (Ea = 105.4 kJ/mol). Trapping of the in-situ-generated ketenes by alcohols to give esters required the addition of a tertiary amine catalyst to prevent competitive [2+2] addition of the ketene to the alkoxyalkyne precursor.

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      A monolith immobilised iridium Cp* catalyst for hydrogen transfer reactions under flow conditions

      • Maria Victoria Rojo* 1
      • Lucie Guetzoyan1
      • Ian. R. Baxendale1 2
      • 1 Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK
      • 2 Department of Chemistry, University of Durham, South Road, Durham, UK
      A monolith immobilised iridium Cp* catalyst for hydrogen transfer reactions under flow conditions

      An immobilised iridium hydrogen transfer catalyst has been developed for use in flow based processing by incorporation of a ligand into a porous polymeric monolithic flow reactor. The monolithic construct has been used for several redox reductions demonstrating excellent recyclability, good turnover numbers and high chemical stability giving negligible metal leaching over extended periods of use.

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      C(sp³)–H functionalisation of N-aryl tetrahydroisoquinolines via an iron-catalysed aerobic nitro-Mannich reaction and continuous flow processing

      • Martin Brzozowski
      • Jose A. Forni
      • G. Paul Savage and Anastasios Polyzos*
      • CSIRO Manufacturing Flagship, Bayview Avenue, Clayton, Australia

      An efficient nitro-Mannich type direct α-C(sp³)–H functionalisation of N-aryl-1,2,3,4-tetrahydroisoquinolines catalysed by simple iron salts in combination with O2 as the terminal oxidant is described. The use of a Teflon AF-2400 membrane Tube-in-Tube reactor under continuous flow conditions allowed for considerable process intensification to be achieved relative to previous batch methods.

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      Facilitating Biomimetic Syntheses of Borrerine Derived Alkaloids by Means of Flow-Chemical Methods

      • Sonja B. KamptmannA
      • Steven V. Ley
      • A Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK

      Flow chemistry is widely used nowadays in synthetic chemistry and has increasingly been applied to complex natural product synthesis. However, to date flow chemistry has not found a place in the area of biomimetic synthesis. Here we show the syntheses of borrerine derived alkaloids, indicating that we can use biomimetic principles in flow to prepare complex architectures in a single step.

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      The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions

      • Steffen Glöckner
      • Duc N. Tran
      • Richard J. Ingham
      • Sabine Fenner
      • Zoe E. Wilson
      • Claudio Battilocchio
      • Steven V. Ley*
      • Department of Chemistry, University of Cambridge, Cambridge, UK

      A rapid flow synthesis of oxazolines and their oxidation to the corresponding oxazoles is reported. The oxazolines are prepared at room temperature in a stereospecific manner, with inversion of stereochemistry, from β-hydroxy amides using Deoxo-Fluor®. The corresponding oxazoles can then be obtained via a packed reactor containing commercial manganese dioxide.

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      Development of a Grignard-Type Reaction for Manufacturing in a Continuous-Flow Reactor

      Fabrice G. J. Odille†§, Anna Stenemyr†§, Fritiof Pontén*‡

      • Pharmaceutical Development R&D, Chemical Science, AstraZeneca, SE-151 85 Södertälje, Sweden
      • Innovative Medicines, Cardiovascular and Metabolic Diseases, Medicinal Chemistry, AstraZeneca R&D, Sweden
      • § SP Process Development, Forskargatan, Sweden

      This paper describes the scale-up of a highly exothermic and fast reaction from a microreactor with an internal volume of less than 1 mL to a mesoreactor with an internal volume of 13.5 mL. The development of a continuous process for manufacturing a ketone from an ester using a Grignard reagent is described. The different steps undertaken and the considerations made to be able to operate in continuous mode and achieve a product output of ca. 0.5 kg are presented.

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      Regioselective Synthesis of 3-Aminoimidazo[1,2-a]-pyrimidines under Continuous Flow Conditions

      • Ashlie J. E. Butler
      • Mark J. Thompson
      • Patrick J. Maydom
      • James A. Newby
      • Kai Guo
      • Harry Adams
      • Beining Chen*
      • Department of Chemistry, University of Sheffield, Sheffield, U.K.

      Multicomponent synthesis of 3-aminoimidazo[1,2-a]pyrimidines usually affords a product mixture containing varying amounts of the corresponding 2-amino regioisomer. Modified methods, particularly microwave heating, have been employed to suppress formation of this side-product, but none of the revised protocols are readily amenable to scale. A continuous flow adaptation was found to offer improved regioselectivity toward the targeted 3-amino regioisomer with significantly shorter reaction times and also widened the scope of the reaction to permit the use of aliphatic aldehyde building blocks.

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      Microwave irradiation and flow chemistry for a straightforward synthesis of piano-stool iron complexes

      • Anastassiya Pagnoux-Ozherelyevaa
      • David Bolienb
      • Sylvain Gaillarda
      • Flavie Peudrua
      • Jean-François Lohiera
      • Richard J. Whitbyb
      • Jean-Luc Renauda
      • aNormandie University, University of Caen Basse Normandie, Laboratoire de Chimie Moléculaire et Thioorganique, CNRS, Caen, France
      • bChemistry, University of Southampton, Southampton, UK

      Two series of piano-stool iron(II) complexes bearing bidentate phosphine or mixed phosphorus–nitrogen ligands have been prepared upon reaction with CpFe(CO)2I or [CpFe(naphthalene)][PF6] under microwave irradiation or using flow chemistry.

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      Glucuronidation of bile acids under flow conditions: design of experiments and Koenigs–Knorr reaction optimization

      • Serena Mostardaa
      • Paolo Filipponia
      • Roccaldo Sardellaa
      • Francesco Venturonia
      • Benedetto Natalinia
      • Roberto Pellicciariab
      • Antimo Gioiello*a
      • aLaboratory of Medicinal and Advanced Synthetic Chemistry (Lab MASC), Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
      • bTES Pharma S.r.l., Corciano, Italy

      An efficient method for the C3-glucuronidation of bile acids is developed under flow conditions. A modular mesoreactor assisted flow set-up was combined with statistical design of experiments to speed up the optimization of the Koenigs–Knorr reaction in terms of yield, regioselectivity, costs, as well as technical and practical standpoints. Using the optimal conditions, selective glucuronidation of naturally occurring bile acids was successfully achieved offering a new, valuable route to C3-glucuronidated bile acids useful for biological, diagnostic and PK/ADMET investigations.

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      A General Continuous Flow Method for Palladium Catalysed Carbonylation Reactions Using Single and Multiple Tube-in-Tube Gas-Liquid Microreactors

      Ulrike Gross1, Peter Koos1, Matthew O'Brien1,2,*, Anastasios Polyzos1,3, Steven V. Ley1

      • 1Whiffen Laboratory, Department of Chemistry, University of Cambridge, Cambridge, UK
      • 2School of Physical and Geographical Sciences, Keele University, Staffordshire, UK
      • 3CSIRO, Materials Science and Engineering, Clayton South, Australia

      A series of continuous flow chemistry processes that facilitate the palladium-catalysed carbonylation of aryl and vinyl iodides and aryl bromides with a range of alkoxy, hydroxy and amino nucleophiles is reported. Harnessing a semipermeable Teflon® AF-2400 Tube-in-Tube assembly, these reactors permit the controlled transport of carbon monoxide into solution at elevated pressure to generate homogeneous flow streams, avoiding some potential issues associated with segmented flow gas-liquid reactors. As the volume of pressurised gas contained within the device is low, the hazards associated with this are potentially mitigated relative to comparable batch processes. We also show how the incorporation of a second in-line gas-flow reactor allows for the sequential introduction of two gases (carbon monoxide and a gaseous nucleophile) into the reaction stream.

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      Consecutive Oxygen-based Oxidations Convert Amines to a-Cyanoepoxides

      • Dmitry B. Ushakova
      • Kerry Gilmore*a
      • Peter H. Seeberger*a,b
      • aMax Planck Institute of Colloids and Interfaces, Potsdam, Germany
      • bInstitute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany

      Tri- or tetrasubstituted α-cyanoepoxides can be rapidly prepared from unactivated amines and malononitrile or methyl cyanoacetate when singlet oxygen, produced in a continuous-flow photoreactor, serves as an oxidant and in situ peroxide source. The hydrogen peroxide generated in amine oxidation epoxidizes an electron deficient olefin intermediate, formed by deaminative Mannich coupling. The corresponding α,α-dicyano- or α-cyano-α-esterepoxides were obtained in good yields (43–82%).

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      Synthesis of a Carprofen Analogue Using a Continuous Flow UV-Reactor

      • Antoine Caron
      • Augusto C. Hernandez-Perez
      • Shawn K. Collins*
      • Department of Chemistry and Centre for Green Chemistr
      • Catalysis, Université de Montréal, Québec, Canada.

      A continuous flow UV light reactor has been constructed using commercially available equipment, and its efficiency was demonstrated by performing a photocyclodehydrogenation reaction to prepare carbazole derivatives of the drug carprofen.

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      Flow Chemistry Meets Advanced Functional Materials

      Dr. Rebecca M. Myers, Daniel E. Fitzpatrick, Dr. Richard M. Turner, Prof. Steven V. Ley*

      • Department of Chemistry, University of Cambridge, Cambridge, UK

      Flow chemistry and continuous processing techniques are beginning to have a profound impact on the production of functional materials ranging from quantum dots, nanoparticles and metal organic frameworks to polymers and dyes. These techniques provide robust procedures which not only enable accurate control of the product material’s properties but they are also ideally suited to conducting experiments on scale. The modular nature of flow and continuous processing equipment rapidly facilitates reaction optimisation and variation in function of the products.

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      Continuous Synthesis of Artemisinin-Derived Medicines

      • Kerry Gilmorea
      • Daniel Kopetzkia
      • Ju Weon Leeb
      • Zoltan Horvathb
      • D. Tyler McQuadea
      • Andreas Seidel-Morgensternb,c
      • Peter H. Seebergera,d
      • aMax-Planck-Institute of Colloids and Interfaces, Department of Biomolecular Systems, Germany
      • bMax-Planck-Institute for Dynamics of Complex Technical Systems, Germany
      • cOtto-von-Guericke-University, Chair for Chemical Process Technology, Germany
      • dFreie Universität Berlin, Institute of Chemistry and Biochemistry, Berlin, Germany

      Described is a continuous, divergent synthesis system which is coupled to continuous purification and is capable of producing four anti-malarial APIs. The system is comprised of three linked reaction modules for photooxidation/cyclization, reduction, and derivatization. A fourth module couples the crude reaction stream with continuous purification to yield pure API.

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      A Continuous-Flow Approach to 3,3,3-Trifluoromethylpropenes: Bringing Together Grignard Addition, Peterson Elimination, Inline Extraction, and Solvent Switching

      • Trevor A. Hamlin
      • Gillian M. L. Lazarus
      • Christopher B. Kelly
      • Nicholas E. Leadbeater*†‡
      • Department of Chemistry, University of Connecticut, United States
      • Department of Community Medicine & Health Care, University of Connecticut Health Center, United States

      A continuous-flow approach to the synthesis of 3,3,3-trifluoromethylpropenes involving Grignard addition of (trimethylsilyl)methylmagnesium chloride to a trifluoromethyl ketone followed by dehydrative desilylation of the α-trifluoromethyl-β-hydroxysilyl alcohol using trimethylsilyl trifluoromethanesulfonate is reported. An inline aqueous/organic extraction and a concomitant solvent switch were key to the success of the methodology. Transition from batch to continuous flow conditions allows for higher yields, shorter reaction times, and facile scale out.

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      Heterogenization of Pd–NHC complexes onto a silica support and their application in Suzuki–Miyaura coupling under batch and continuous flow conditions

      • Alberto Martíneza
      • Jamin L. Krinskya
      • Itziar Peñafiela
      • Sergio Castillónb
      • Konstantin Loponovc
      • Alexei Lapkinc
      • Cyril Godard*a
      • Carmen Claver*a
      • aDepartment of Physical and Inorganic Chemistry, Universitat Rovira i Virgili, Tarragona, Spain
      • bDepartment of Analytical and Organic Chemistry, Universitat Rovira i Virgili, Tarragona, Spain
      • cDepartment of Chemical Engineering and Biotechnology, University of Cambridge, , Cambridge, UK

      The heterogenisation of a new family of Pd–NHC complexes is reported via a straightforward and efficient synthetic procedure. These silica-immobilised materials were successfully applied as catalysts in the Suzuki–Miyaura coupling of aryl chlorides and bromides under mild conditions. The materials exhibited improved stability when the catalytic reaction was run under anhydrous conditions and could be recycled up to five times without significant loss of activity. When the reaction was run within a continuous flow microreactor, these catalysts showed good activity after at least two hours on stream.

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      Glycosylation with N-acetyl glycosamine donors using catalytic iron(III) triflate: from microwave batch chemistry to a scalable continuous-flow process

      • Amandine Xolina
      • Arnaud Stévenina
      • Mathieu Pucheaultb
      • Stéphanie Norsikiana
      • François-Didier Boyer*ac
      • Jean-Marie Beau*ad
      • aCentre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette, France
      • bInstitut des Sciences Moléculaires, CNRS-Université de Bordeaux, Talence, France
      • cInstitut Jean-Pierre Bourgin, UMR1318 INRA-AgroParisTech, Versailles, France
      • dUniversité Paris-Sud and CNRS, Laboratoire de Synthèse de Biomolécules, Institut de Chimie Moléculaire et des Matériaux, Orsay, France

      Efficient and highly selective glycosylation reactions of peracetylated β-D-N-acetyl gluco- and galactosamine are described using catalytic iron(III) triflate under microwave conditions or in a continuous flow process. Simple β-glycosides and β-(1 → 6), β-(1 → 2) and β-(1 → 3) linked disaccharides bearing various protecting groups were obtained in high yields. Insights into the glycosylation mechanism are discussed.

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      Multistep Flow Synthesis of 5-Amino-2-aryl-2H-[1,2,3]-triazole-4-carbonitriles

      YDr. Jérôme Jacq, Dr. Patrick Pasau*

      • UCB Biopharma, Avenue de l'Industrie, 1420 Braine l'Alleud (Belgium)

      1,2,3-Triazole has become one of the most important heterocycles in contemporary medicinal chemistry. The development of the copper-catalyzed Huisgen cycloaddition has allowed the efficient synthesis of 1-substituted 1,2,3-triazoles. However, only a few methods are available for the selective preparation of 2-substituted 1,2,3-triazole isomers. In this context, we decided to develop an efficient flow synthesis for the preparation of various 2-aryl-1,2,3-triazoles. Our strategy involves a three-step synthesis under continuous-flow conditions that starts from the diazotization of anilines and subsequent reaction with malononitrile, followed by nucleophilic addition of amines, and finally employs a catalytic copper(II) cyclization. Potential safety hazards associated with the formation of reactive diazonium species have been addressed by inline quenching. The use of flow equipment allows reliable scale up processes with precise control of the reaction conditions. Synthesis of 2-substituted 1,2,3-triazoles has been achieved in good yields with excellent selectivities, thus providing a wide range of 1,2,3-triazoles.

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      Versatile, High Quality and Scalable Continuous Flow Production of Metal-Organic Frameworks

      • Marta Rubio-Martinez
      • Michael P. Batten
      • Anastasios Polyzos
      • Keri-Constanti Carey
      • James I. Mardel
      • Kok-Seng Lim
      • Matthew R. Hill
      • CSIRO Materials Science and Engineering, Australia

      Further deployment of Metal-Organic Frameworks in applied settings requires their ready preparation at scale. Expansion of typical batch processes can lead to unsuccessful or low quality synthesis for some systems. Here we report how continuous flow chemistry can be adapted as a versatile route to a range of MOFs, by emulating conditions of lab-scale batch synthesis. This delivers ready synthesis of three different MOFs, with surface areas that closely match theoretical maxima, with production rates of 60 g/h at extremely high space-time yields.

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      Continuous Flow Magnesiation of Functionalized Heterocycles and Acrylates with TMPMgCl·LiCl

      Dr. Trine P. Petersen, Matthias R. Becker, Prof. Dr. Paul Knochel*

      • Ludwig-Maximilians-Universität München, Department Chemie, München, Germany

      A flow procedure for the metalation of functionalized heterocycles (pyridines, pyrimidines, thiophenes, and thiazoles) and various acrylates using the strong, non-nucleophilic base TMPMgCl⋅LiCl is reported. The flow conditions allow the magnesiations to be performed under more convenient conditions than the comparable batch reactions, which often require cryogenic temperatures and long reaction times. Moreover, the flow reactions are directly scalable without further optimization. Metalation under flow conditions also allows magnesiations that did not produce the desired products under batch conditions, such as the magnesiation of sensitive acrylic derivatives. The magnesiated species are subsequently quenched with various electrophiles, thereby introducing a broad range of functionalities.

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      Continuous Synthesis of Organozinc Halides Coupled to Negishi Reactions

      • Nerea Alonso2,3
      • L. Zane Miller1
      • Juan de M. Muñoz2
      • Jesus Alcázar2,*
      • D. Tyler McQuade1,*
      • 1Department of Chemistry and Biochemistry, Florida State University, USA
      • 2Janssen Research and Development, Janssen-Cilag, Toledo, Spain
      • 3Facultad de Química, Universidad de Castilla-La Mancha, Spain

      The Negishi cross-coupling is a powerful C[BOND]C bond forming reaction. The method is less commonly used relative to other cross-coupling methods in part due to lack of availability of organozinc species. While organozinc species can be prepared, problems with reproducibility and handling of these sensitive species can complicate these reactions. Herein, we describe the continuous formation, using an activated packed-bed of metallic zinc, and subsequent use of organozinc halides. We demonstrate that a single column of zinc can provide excellent yields of organozinc halides and that they can be used downstream in subsequent Negishi cross-couplings. The preparation of the zinc column and the scope of the reaction are discussed.

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      Continuous Flow Synthesis of Thieno[2,3-c]isoquinolin-5(4H)-one Scaffold: A Valuable Source of PARP-1 Inhibitors

      • Paolo Filipponi
      • Carmine Ostacolo
      • Ettore Novellino
      • Roberto Pellicciari†§
      • Antimo Gioiello*†
      • Dipartimento di Scienze Farmaceutiche, Università di Perugia, Via del Liceo 1, I-06123 Perugia, Italy
      • Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, Napoli, Italy §TES Pharma S.r.l., Corciano (Perugia), Italy

      An efficient multistep method for the continuous flow synthesis of thieno[2,3-c]isoquinolin-5(4H)-one-A (TIQ-A), an important pharmacological tool and building block for PARP-1 inhibitors, has been developed. The synthesis involves a Suzuki coupling reaction to generate 3-phenylthiophene-2-carboxylic acid which is transformed into the corresponding acyl azide and readily cyclized by a thermal Curtius rearrangement. A statistical design of experiments (DoE) was employed as a valuable support for decision-making of further experiments enabling the development of a robust and reliable protocol for large-scale preparation. As a result, the reactions are facile, safe, and easy to scale-up. The large-scale applicability of this improved flow method was tested by conducting the reactions on multigram scale to produce the desired product in high yield and quality for biopharmacological appraisals.

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      First Example of a Continuous-Flow Carbonylation Reaction Using Aryl Formates as CO Precursors

      • Nerea Alonso1,3
      • Juan de Muñoz1
      • Brecht Egle2
      • Johannes L. Vrijdag2
      • Wim M. De Borggraeve2
      • Antonio de la Hoz3
      • Angel Díaz-Ortiz3
      • Jesús Alcázar1
      • 1Janssen Research and Development, Janssen-Cilag Department of Medicinal Chemistry S.A., Toledo, Spain
      • 2Molecular Design and Synthesis University of Leuven, Department of Chemistry, Heverlee Belgium
      • 3Universidad de Castilla-La Mancha Facultad de Ciencias y Tecnologías Químicas Real, Spain

      The first continuous flow carbonylation reaction using aryl formates as CO precursor is reported. The reaction is practical, scalable and high yielding. The use of a flow protocol safely allows expanding the scope to activated chlorides, nitrogen heterocycles and to the selective introduction of an ester group in dihalo-derivatives. Further selective reduction of the ester formed to an aldehyde in flow is also described.

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      Integration of enabling methods for the automated flow preparation of piperazine-2-carboxamide

      • Richard J. Ingham1
      • Claudio Battilocchio1
      • Joel M. Hawkins2
      • Steven V. Ley1
      • 1 Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK
      • 2 Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA

      Here we describe the use of a new open-source software package and a Raspberry Pi® computer for the simultaneous control of multiple flow chemistry devices and its application to a machine-assisted, multi-step flow preparation of pyrazine-2-carboxamide – a component of Rifater®, used in the treatment of tuberculosis – and its reduced derivative piperazine-2-carboxamide.

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      Seamless Integration of Dose-Response Screening and Flow Chemistry: Efficient Generation of Structure–Activity Relationship Data of ?-Secretase (BACE1) Inhibitors

      Dr. Michael Werner1,*, Christoph Kuratli1, Dr. Rainer E. Martin1,*, Dr. Remo Hochstrasser1, David Wechsler1, Dr. Thilo Enderle1, Dr. Alexander I. Alanine1, Prof. Dr. Horst Vogel2

      • 1 Medicinal Chemistry, Small Molecule Research, Pharma Research & Early Development (pRED), F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 Basel (Switzerland)
      • 2 Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology of Lausanne (EPFL), Station 6, 1015 Lausanne (Switzerland)

      Drug discovery is a multifaceted endeavor encompassing as its core element the generation of structure-activity relationship (SAR) data by repeated chemical synthesis and biological testing of tailored molecules. Herein, we report on the development of a flow-based biochemical assay and its seamless integration into a fully automated system comprising flow chemical synthesis, purification and in-line quantification of compound concentration. This novel synthesis-screening platform enables to obtain SAR data on b-secretase (BACE1) inhibitors at an unprecedented cycle time of only 1 h instead of several days. Full integration and automation of industrial processes have always led to productivity gains and cost reductions, and this work demonstrates how applying these concepts to SAR generation may lead to a more efficient drug discovery process.

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      Sequential flow process for the controlled polymerisation and thermolysis of RAFT-synthesised polymers

      • CH Hornung
      • A Postma
      • S Saubern
      • J Chiefari
      • CSIRO Materials Science and Engineering, Victoria, Australia

      The RAFT (Reversible Addition-Fragmentation Chain Transfer) process greatly enhances the control over radical polymerisations, while leaving behind a thiocarbonylthio end-group. Thermolysis presents a convenient and efficient way of removing the thiocarbonylthio end-group from RAFT polymers, without the use of additional reagents. This paper describes a simple two-step flow process for the synthesis of RAFT polymers followed by the subsequent removal of the RAFT end-group via thermolysis, without the need for isolating intermediates. A range of different polymers based on styrene, acrylates, methacrylates and acrylamides were synthesised with different RAFT agents and successfully tested for thermolysis at temperatures between 220 and 250 °C in a stainless steel tube flow reactor, resulting in complete removal of thiocarbonylthio end-groups.

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      Robust and reusable supported palladium catalysts for cross-coupling reactions in flow

      William R. Reynoldsab, Pawel Plucinskibc, Christopher G. Frost*ab

      •   * Corresponding authors
      • a Centre for Sustainable Chemical Technologies, University of Bath, Claverton Down, Bath, UK
      • b Department of Chemistry, University of Bath, Claverton Down, Bath, UK
      • c Department of Chemical Engineering, University of Bath, Claverton Down, Bath, UK

      Two novel polymer encapsulated silica supported palladium catalysts have been prepared and shown to be highly active, robust and recyclable catalysts for Heck and Suzuki–Miyaura cross coupling reactions under continuous flow conditions. They were demonstrated to give excellent conversions of both electron rich and electron deficient substrates and the catalysts were used for over 50 hours continuous operation without any appreciable decrease in catalytic activity and low levels of Pd leaching measured by ICP-MS.

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      Continuous-Flow Oxidative Cyanation of Primary and Secondary Amines Using Singlet Oxygen

      Dmitry B. Ushakov, Kerry Gilmore, Daniel Kopetzki, D. Tyler McQuade, Peter H. Seeberger

      • 1Department für Biomolekulare Systeme, Max-Planck-Institut für Kolloid- und Grenzflächenforschung, Potsdam, Germany
      • 2Institut für Chemie und Biochemie, Freie Universität Berlin, Berlin, Germany
      • 3Department of Chemistry and Biochemistry, Florida State University, Tallahassee, USA

      Primary and secondary amines can be rapidly and quantitatively oxidized to the corresponding imines by singlet oxygen. This reactive form of oxygen was produced using a variable-temperature continuous-flow LED-photoreactor with a catalytic amount of tetraphenylporphyrin as the sensitizer. α-Aminonitriles were obtained in good to excellent yields when trimethylsilyl cyanide served as an in situ imine trap. At 25°C, primary amines were found to undergo oxidative coupling prior to cyanide addition and yielded secondary α-aminonitriles. Primary α-aminonitriles were synthesized from the corresponding primary amines for the first time, by an oxidative Strecker reaction at –50 °C. This atom-economic and protecting-group-free pathway provides a route to racemic amino acids, which was exemplified by the synthesis of tert-leucine hydrochloride from neopentylamine.

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      Flow synthesis of a versatile fructosamine mimic and quenching studies of a fructose transport probe

      • Matthew B. Plutschack1,2
      • D. Tyler McQuade1,2
      • Giulio Valenti2
      • Peter H. Seeberger2
      • 1Department of Chemistry and Biochemistry, Florida State University, USA
      • 2Max Planck Institute of Colloids and Interfaces, Germany

      We describe the synthesis of 1-amino-2,5-anhydro-D-mannose (“mannitolamine”), a key intermediate to the 7-nitro-1,2,3-benzadiazole conjugate (NBDM), using commercially available fluidic devices to increase the throughput. The approach is the first example of a flow-based Tiffeneau–Demjanov rearrangement. Performing this step in flow enables a ~64-fold throughput enhancement relative to batch. The flow process enables the synthesis to be accomplished three times faster than the comparable batch route. The high throughput enabled the production of larger quantities of the fluorescent fructose transport probe NBDM, enabling us to measure key photophysical properties that will facilitate future uptake studies.

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      The Fit For Purpose Development of S1P1 Receptor Agonist GSK2263167 Using a Robinson Annulation and Saegusa Oxidation to Access an Advanced Phenol Intermediate

      • Robert M. Harris
      • Benjamin I. Andrews
      • Stacy Clark
      • Jason W. B. Cooke
      • John C. S. Gray
      • Stephanie Q. Q. Ng
      • Chemical Development, GlaxoSmithKline Research and Development Ltd., UK

      A fit for purpose approach has been adopted in order to develop a robust, scalable route to the S1P1 receptor agonist, GSK2263167. The key steps include a Robinson ring annulation followed by a Saegusa oxidation, providing rapid access to an advanced phenol intermediate. Despite the use of stoichiometric palladium acetate for the Saegusa oxidation, near complete recovery of the palladium has been demonstrated. The remaining steps have been optimised including the removal of all chromatography. An alternative to the Saegusa oxidation is described as well as the development of a flow process to facilitate further scale-up of the amidoxime preparation using hydroxylamine at elevated temperature.

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      Flow-Based, Cerium Oxide Enhanced, Low-Level Palladium Sonogashira and Heck Coupling Reactions by Perovskite Catalysts

      Claudio Battilocchio1, Benjamin N. Bhawal1, Rajeev Chorghade1, Benjamin J. Deadman1, Joel M. Hawkins2, Steven V. Ley1

      • 1 Innovative Technology Centre, Department of Chemistry, University of Cambridge, UK
      • 2 Pfizer Worldwide Research & Development, Groton, USA

      A flow chemistry procedure for Sonogashira and Heck cross-coupling reactions using a low-level palladium perovskite catalyst (LaFe0.95Pd0.05O3) deposited on cerium oxide is reported. The catalyst was generated in situ at high temperature using a flow platform. The system could be applied to a wide range of functionalised substrates, allowing clean and fast delivery of the products within a few minutes (10–30 min), after scavenging with thiourea polymer (QP-TU) and sulfonic acid resin (QP-SA). The use of an in-line evaporator/solvent switching device allowed us to recover the solvent and transport the material into the following stage. The catalyst could be continuously used for at least 24 h, without any noticeable decrease in the catalytic efficiency. In one example the system was scaled to deliver 10 mmol of product.

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

      • Trevor A. Hamlin
      • Nicholas E. Leadbeater
      • Department of Chemistry, University of Connecticut, USA

      An apparatus is reported for real-time Raman monitoring of reactions performed using continuous-flow processing. Its capability is assessed by studying four reactions, all involving formation of products bearing α,β-unsaturated carbonyl moieties; synthesis of 3-acetylcoumarin, Knoevenagel and Claisen–Schmidt condensations, and a Biginelli reaction. In each case it is possible to monitor the reactions and also in one case, by means of a calibration curve, determine product conversion from Raman spectral data as corroborated by data obtained using NMR spectroscopy.

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      Continuous Flow-Processing of Organometallic Reagents Using an Advanced Peristaltic Pumping System and the Telescoped Flow Synthesis of (E/Z)-Tamoxifen

      • Philip R D Murray
      • Duncan L Browne
      • Julio C Pastre
      • Chris Butters
      • Duncan Guthrie
      • Steven V Ley
      • Department of Chemistry, University of Cambridge, UK Instituto de Química, University of Campinas, Brazil Vapourtec Ltd, UK
      continuous flow processing of organometallic reagents

      A new enabling technology for the pumping of organometallic reagents such as n-butyllithium, Grignard reagents, and DIBAL-H is reported, which utilises a newly developed, chemically resistant, peristaltic pumping system. Several representative examples of its use in common transformations using these reagents, including metal–halogen exchange, addition, addition–elimination, conjugate addition, and partial reduction, are reported along with examples of telescoping of the anionic reaction products. This platform allows for truly continuous pumping of these highly reactive substances (and examples are demonstrated over periods of several hours) to generate multigram quantities of products. This work culminates in an approach to the telescoped synthesis of (E/Z)-tamoxifen using continuous-flow organometallic reagent-mediated transformations.

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      Biotransformation with whole microbial systems in a continuous flow reactor: resolution of (RS)-flurbiprofen using Aspergillus oryzae by direct esterification with ethanol in organic solvent

      • Lucia Tamborinia
      • Diego Romanob
      • Andrea Pintoa
      • Martina Contentea
      • Maria C. Iannuzzia
      • Paola Contia
      • Francesco Molinarib
      • a Dipartimento di Scienze Farmaceutiche, Universitá degli Studi di Milano, Italy
      • b Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente (DEFENS), Universitá degli Studi di Milano, Italy

      Cell-bound lipases of dry mycelium of Aspergillus oryzae were used in organic solvent for the resolution of racemic flurbiprofen by direct esterification with ethanol in a flow-chemistry reactor. Under flow conditions a significant reduction of the reaction time and an increase of the enantioselectivity were achieved compared to the batch mode. Moreover, the process was implemented by adding an in-line purification step integrated with the racemization of the unreacted flurbiprofen directly into a polymer-supported resin.

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      Porous, functional, poly(styrene-co-divinylbenzene) monoliths by RAFT polymerization

      • Kristine J. Barlow (née Tan)
      • Xiaojuan Hao
      • Timothy C. Hughes
      • Oliver E. Hutt
      • Anastasios Polyzos
      • Kathleen A. Turner
      • Graeme Moad
      • Commonwealth Scientific and Industrial Research Organisation (CSIRO), Materials Science & Engineering, Australia

      Herein we provide the first report of a new method for the preparation of porous functional poly(styrene-co-divinylbenzene) monoliths by use of reversible addition–fragmentation chain transfer (RAFT) polymerization. The method, exemplified by styrene–divinylbenzene copolymerization in the presence of 2-cyano-2-propyl dodecyl trithiocarbonate, provides control over polymerization kinetics, monolith morphology and surface functionality. Kinetic studies of monolith formation show a period of slow copolymerization, with a rate similar to RAFT homopolymerization of styrene, followed by rapid copolymerization, with a rate similar to that observed in conventional styrene–divinylbenzene copolymerization. The time to onset of rapid polymerization (gelation) and the monolith morphology depend strongly on the RAFT agent concentration. The RAFT-synthesized monoliths show a modified morphology with smaller pores and polymer globules when compared to non-RAFT monoliths, but importantly retain good flow properties. Retention of the thiocarbonylthio group within the monolith structure in an active form for surface-functionalization of the polymeric monoliths is demonstrated by the successful RAFT “grafting from” polymerization of (4-vinylphenyl)boronic acid. These functional monoliths have potential applications in chromatography and flow chemistry.

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

      • Kimberley A. Roper1
      • Malcolm B. Berry2
      • Steven V. Ley1
      • 1 Innovative Technology Centre, Department of Chemistry, University of Cambridge, Cambridge, U.K.
      • 2 GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.

      The application of a monolithic form of triphenylphosphine to the Ramirez gem-dibromoolefination reaction using flow chemistry techniques is reported. A variety of gem-dibromides were synthesised in high purity and excellent yield following only removal of solvent and no further off-line purification. It is also possible to perform the Appel reaction using the same monolith and the relationship between the mechanisms of the two reactions is discussed.

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      Continuous Flow Synthesis of Coumarin

      Anbang Chen1, Xin Li1, Yangzhi Zhou1, Lingling Huang2, Zheng Fang2, Haifeng Gan1, Kai Guo1

      • 1 College of Biotechnology and Pharmaceutical Engineering, Nanjing University of Technology 2 School of Pharmceutical Sciences, Nanjing University of Technology

      Flow chemistry, as a rapidly emerging technology, is exploited to provide a safe and scalable route for the pharmaceutically interesting coumarin. Here, a continuous flow approach for the generation of coumarin is reported, which relies on the two connected coil reactors design. The synthesis of coumarin has been performed successfully in high conversion on small scale and can be scaled up substantially.

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      Synthesis of All Four Stereoisomers of 3-(tert-Butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic Acid

      • Bettina Bakonyi
      • Markus Furegati*‡
      • Christian Kramer§
      • Luigi La Vecchia
      • Flavio Ossola
      • Doetsch Grether AG, Falkensteinerstrasse 37, 4132 Muttenz, Switzerland
      • Preparations Laboratories, Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Klybeckstrasse 141, 4057 Basel,Switzerland
      • § Institute of General, Inorganic and Theoretical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria

      A synthesis of all four stereoisomers of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid has been developed, thereby significantly shortening the known literature procedures for the syntheses of these unnatural amino acids. With a simple adjustment of the reaction conditions, we were able to obtain either pure cis or trans acid. Optical resolution was accomplished via diastereomeric salt formation or alternatively via chromatography on a chiral stationary phase. Finally, ab initio calculations gave an explanation for the observed cis selectivity in the initial step.

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      The rapid generation of isothiocyanates in flow

      • Marcus Baumann
      • Ian R. Baxendale
      • Department of Chemistry, University of Durham, U.K.

      Isothiocyanates are versatile starting materials for a wide range of chemical reactions. However, their high nucleophilic susceptibility means they are best prepared and used immediately. We report here on a flow platform for the fast and efficient formation of isothiocyanates by the direct conversion of easily prepared chloroximes. To expedite this chemistry a flow insert cartridge containing two immobilised reagents is used to affect the chemical transformation which typically eliminates the requirements for any conventional work-up or purification of the reaction stream.

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      Continuous synthesis of pyridocarbazoles and initial photophysical and bioprobe characterization

      • D. Tyler McQuade*ab
      • Alexander G. O'Briena
      • Markus Dörrc
      • Rajathees Rajaratnamc
      • Ursula Eisoldd
      • Bopanna Monnandaa
      • Tomoya Nobutaa
      • Hans-Gerd Löhmannsröbend
      • Eric Meggersc
      • Peter H. Seebergerae
      • a Department for Biomolecular Systems, Max Planck Institute for Colloids and Interfaces
      • b Department of bChemistry and Biochemistry, Florida State University
      • c Fachbereich Chemie, Philipps-Universität Marburg
      • d Potsdam Institut für Chemie
      • e Freie Universität Berlin
      Continuous synthesis of pyridocarbazoles and initial photophysical and bioprobe characterization

      Pyridocarbazoles when ligated to transition metals yield high affinity kinase inhibitors. While batch photocyclizations enable the synthesis of these heterocycles, the non-oxidative Mallory reaction only provides modest yields and difficult to purify mixtures. We demonstrate here that a flow-based Mallory cyclization provides superior results and enables observation of a clear isobestic point. The flow method allowed us to rapidly synthesize ten pyridocarbazoles and for the first time to document their interesting photophysical attributes. Preliminary characterization reveals that these molecules might be a new class of fluorescent bioprobe.

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      Microwave heating and conventionally-heated continuous-flow processing as tools for performing cleaner palladium-catalyzed decarboxylative couplings using oxygen as the oxidant – a proof of principle study

      Nicholas E. Leadbeater1, DiAndra M. Rudzinski1

      • 1 Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, CT 06269, USA

      A microwave unit interfaced with a gas-loading accessory is used as a tool for facilitating the palladium-catalyzed decarboxylative Heck reaction of 2,6-dimethoxybenzoic acid and methyl acrylate, using molecular oxygen as the oxidant. The reaction is complete in less time and at a lower catalyst loading than when using conventional approaches. The reaction is scaled up using continuous-flow processing, employing a reactor in which both gas input and heating can be performed simultaneously. An 86% isolated product yield is obtained. This proof-of-principle study paves the way for the technology to be used in other cases of these increasingly popular decarboxylative coupling reactions.

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

      Nida Ambreen, Ravi Kumar, Thomas Wirth

      • Innovative Technology Centre, Cardiff University, School of Chemistry, Park Place, Cardiff, UK

      Aryl- and heteroarylcyclobutenone rearrangements proceed in excellent yield under continuous-flow conditions. The former shows a Hammett correlation with σI providing strong evidence that electrocyclisation is the rate-determining step and has a late transition state. The reaction has been modelled by using DFT and CCSD(T) methods, with the latter giving excellent correlation with the experimental rate constant. A short and efficient total synthesis of cribrostatin 6, an anti-neoplastic and anti-microbial agent, provides a topical demonstration of the value of this method.

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      First Example of Alkyl-Aryl Negishi Cross-Coupling in Flow: Mild, Efficient and Clean Introduction of Functionalized Alkyl Groups

      • Brecht Egle2
      • Juan de Muñoz1
      • Nerea Alonso1
      • Wim M. De Borggraeve2
      • Antonio de la Hoz3
      • Angel Díaz-Ortiz3
      • Jesús Alcázar1
      • 1Janssen Research and Development Department of Medicinal Chemistry Janssen-Cilag, Toledo Spain
      • 2Department of Chemistry, Molecular Design and Synthesis University of Leuven, Heverlee Belgium
      • 3Universidad de Castilla-La Mancha Facultad de Ciencias y Tecnologías Químicas, Spain

      The first example of an alkyl–aryl Negishi coupling in a practical, sustainable, and high-yielding process using a silica-supported catalyst in flow is described. Excellent conversions and good functional group compatibility were obtained under very mild conditions. Functionalized alkyl groups were also introduced to provide access to synthetically useful molecules and to demonstrate the versatility of the method. The scalability was assessed, and a throughput of 7.5 mmol/h of processed substrate was achieved. All crude products were free from phosphine derivatives and ready for use in subsequent reaction steps.

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

      • Helga Seyler
      • Jegadesan Subbiah
      • David J. Jones
      • Andrew B. Holmes
      • Wallace W. H. Wong*
      • School of Chemistry, Bio21 Institute, University of Melbourne, 30 Flemington Road, Parkville, Victoria 3010, Australia
      • *Corresponding author

      There is an increasing demand for organic semiconducting materials with the emergence of organic electronic devices. In particular, large-area devices such as organic thin-film photovoltaics will require significant quantities of materials for device optimization, lifetime testing and commercialization. Sourcing large quantities of materials required for the 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 of the molecular weight was demonstrated for the first time in flow for conjugated polymers by accurate addition of catalyst to the monomer solution. The P3HT samples synthesized in flow showed comparable performance to commercial P3HT samples in bulk heterojunction solar cell devices.

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      Integrated Synthesis and Testing of Substituted Xanthine Based DPP4 Inhibitors: Application to Drug Discovery

      • Werngard Czechtizky
      • Jurgen Dedio
      • Bimbisar Desai
      • Karen Dixon
      • Elizabeth Farrant
      • Qixing Feng Trevor Morgen
      • David M Parry
      • Manoj K. Ramjee
      • Christopher N. Selway
      • Thorsten Schmidt
      • Gary J. Tarver
      • Adrian G. Wright
      • Sanofi-Aventis, Frankfurt, Germany. Cyclofluidic Ltd., U.K.

      A novel integrated discovery platform has been used to synthesize and biologically assay a series of xanthine-derived dipeptidyl peptidase 4 (DPP4) antagonists. Design, synthesis, purification, quantitation, dilution, and bioassay have all been fully integrated to allow continuous automated operation. The system has been validated against a set of known DPP4 inhibitors and shown to give excellent correlation between traditional medicinal chemistry generated biological data and platform data. Each iterative loop of synthesis through biological assay took two hours in total, demonstrating rapid iterative structure–activity relationship generation.

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      Applying Flow Chemistry: Methods, Materials, and Multistep Synthesis

      • D. Tyler McQuade1 3
      • Peter H. Seeberger1 2
      • 1 Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces
      • 2 Institute for Chemistry and Biochemistry, Freie Universität Berlin,
      • 3 Department of Chemistry and Biochemistry, Florida State University
      Applying Flow Chemistry: Methods, Materials and Multistep Synthesis

      The synthesis of complex molecules requires control over both chemical reactivity and reaction conditions. While reactivity drives the majority of chemical discovery, advances in reaction condition control have accelerated method development/discovery. Recent tools include automated synthesizers and flow reactors. In this Synopsis, we describe how flow reactors have enabled chemical advances in our groups in the areas of single-stage reactions, materials synthesis, and multistep reactions. In each section, we detail the lessons learned and propose future directions.

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      Continuous flow macrocyclization at high concentrations: synthesis of macrocyclic lipids

      Anne-Catherine Bédard, Sophie Régnie, Shawn K. Collins

      • Département de Chimie, Centre for Green Chemistry, Catalysis, Université de Montréal, Montréal, Canada

      A phase separation/continuous flow macrocyclization protocol eliminates the need for high-dilution conditions and can be used to prepare gram quantities of biologically relevant macrocyclic lipid structures. The method presents several green advantages towards macrocycle synthesis: (1) the prevention of unwanted oligomers and waste, (2) a reduction in the large quantities of toxic, volatile organic solvents and (3) the use of PEG as an environmentally benign reaction media. Macrocycles could be synthesized in high yields (up to 99%) in short reaction times (1.5 h) and on gram scales without the need to alter the reaction conditions.

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      Continuous Synthesis and Use of N-Heterocyclic Carbene Copper(I) Complexes from Insoluble Cu2O

      • Suzanne M. Opalka1
      • Jin Kyoon Park3
      • Ashley R. Longstreet2
      • D. Tyler McQuade2
      • 1Department of Chemistry and Biochemistry, Florida State University, USA
      • 2Department of Chemistry and Chemical Biology, Cornell University, USA
      • 3Department of Chemistry and Chemical Institute for Functional Materials, Pusan National University, Korea

      It is demonstrated that homogeneous N-heterocyclic carbene–copper(I)-chloride complexes can be prepared continuously by flowing NHC precursors through a packed bed of solid Cu2O suspended in molecular sieves. The method enables the synthesis of a wide range of complexes including those that are challenging to prepare using standard approaches. Our strategy enables both sustained output of complex production for long-term catalytic reactions (greater than 5 h) and for generation of gram quantities for storage (greater than 1 g of complex in ∼16 min).

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      Ozonolysis of some complex organic substrates in flow

      • M. D. Roydhouse1
      • W. B. Motherwell1
      • A. Constantinou2
      • A. Gavriilidis2
      • R. Wheeler3
      • K. Down3
      • I. Campbell3
      • 1Dept of Chemistry, University College London, UK
      • 2Dept of Chemical Engineering, University College London, UK
      • 3GSK, Stevenage, UK

      The ozonolysis of several organic substrates to give carbonyl compounds, carboxylic acids and nicotinic acids in flow using a standard lab-scale flow system equipped with a cooled flow cell was examined. Alkyl and aryl alkenes showed good conversion (49–99%) to the corresponding aldehydes and ketones utilising an “in flow” quench of triphenylphosphine. The ozonolysis of either 2 or 3-substituted furans obtained furnished a variety of carboxylic acids including the pharmaceutically important oxetane-3-carboxylic acids in two steps from furan and oxetan-3-one. Substituted benzoic acids were generated with high yields in two steps from aryl iodides. The non-selective ozonolysis of quinolines is known to give 2,3-dicarbonyl substituted pyridines, herein we report the selective ozonolysis of 8-hydroquinoline to give 3-[(1E)-3-oxoprop-1-en-1-yl]pyridine-2-carboxylic acid using flow techniques.

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      Synthesis of Carbohydrate-Functionalised Sequence-Defined Oligo(amidoamine)s by Photochemical ThiolEne Coupling in a Continuous Flow Reactor

      Felix Wojcik1,2, Alexander G. O'Brien1,2, Sebastian Götze1,2, Peter H. Seeberger1,2, Laura Hartmann1,2

      • 1Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam (Germany)
      • 2Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin (Germany)

      Poly/oligo(amidoamine)s (PAAs) have recently been recognised for their potential as well-defined scaffolds for multiple carbohydrate presentation and as multivalent ligands. Herein, we report two complimentary strategies for the preparation of such sequence-defined carbohydrate-functionalised PAAs that use photochemical thiol[BOND]ene coupling (TEC) as an alternative to the established azide–alkyne cycloaddition (“click”) reaction. In the first approach, PAAs that contained multiple olefins were synthesised on a solid support from a new building block and subsequent conjugation with unprotected thio-carbohydrates. Alternatively, a pre-functionalised building block was prepared by using TEC and assembled on a solid support to provide a carbohydrate-functionalised PAA. Both methods rely on the use of a continuous flow photoreactor for the TEC reactions. This system is highly efficient, owing to its short path length, and requires no additional radical initiator. Performing the reactions at 254 nm in Teflon AF-2400 tubing provides a highly efficient TEC procedure for carbohydrate conjugation, as demonstrated in the reactions of O-allyl glycosides with thiols. This method allowed the complete functionalisation of all of the reactive sites on the PAA backbone in a single step, thereby obtaining a defined homogeneous sequence. Furthermore, reaction at 366 nm in FEP tubing in the flow reactor enabled the large-scale synthesis of an fluorenylmethyloxycarbonyl (Fmoc)-protected glycosylated building block, which was shown to be suitable for solid-phase synthesis and will also allow heterogeneous sequence control of different carbohydrates along the oligomeric backbone. These developments enable the synthesis of sequence-defined carbohydrate-functionalised PAAs with potential biological applications.

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      Continuous-flow generation of diazoesters and their direct use in S-H and P-H insertion reactions: synthesis of a-sulfanyl, a-sulfonyl and a-phosphono carboxylates

      • Hannah E. Bartrum1
      • David C. Blakemore2
      • Christopher J. Moody1
      • Christopher J. Hayes1
      • 1School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
      • 2Pfizer Neusentis, The Portway Building, Granta Park, Cambridge, CB21 6GS, UK

      The synthesis of α-sulfanyl, α-sulfonyl, and α-phosphono carboxylates has been achieved using a two-step procedure involving the in-flow generation of diazoesters from sulfonylhydrazones, via Bamford–Stevens elimination, and then subsequent S–H, sulfinate, and P–H carbene insertion reactions. The method for α-sulfonyl ester is particularly noteworthy as it represents a very atom economic (‘green’) way to access the products, and it completely avoids the use of alkyl halides.

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      Synthesis of RAFT Block Copolymers in a Multi-Stage Continuous Flow Process Inside a Tubular Reactor

      • Christian H. Hornung
      • Xuan Nguyen
      • Stella Kyi
      • John Chiefari
      • Simon Saubern
      • CSIRO Materials Science & Engineering, Victoria, Australia.

      This work describes a multi-stage continuous flow polymerisation process for the synthesis of block copolymers using the RAFT polymerization method. The process retains all the benefits and versatility of the RAFT method and has been adapted for a series of monomer combinations, including acrylates, acrylamides, and vinyl monomers. It resulted in polymers with molecular weights between 13500 and 34100 g mol–1, and dispersities typically between 1.21 and 1.58. Different architectures were prepared (including combinations of hydrophilic and hydrophobic blocks) which are soluble in a range of different solvents including aqueous and organic media.

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      An expeditious synthesis of imatinib and analogues utilising flow chemistry methods

      • Mark D Hopkin
      • Ian Baxendale
      • Steven.V.Ley
      • Dept of Chemistry, University of Cambridge, UK

      A flow-based route to imatinib, the API of Gleevec, was developed and the general procedure then used to generate a number of analogues which were screened for biological activity against Abl1. The flow synthesis required minimal manual intervention and was achieved despite the poor solubility of many of the reaction components.

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      A Multi-Step Continuous Flow Process for the N-Demethylation of Alkaloids

      • Yuji Nakano1
      • G. Paul Savage1
      • Simon Saubern1
      • Peter J. Scammells2
      • Anastasios Polyzos1
      • 1 CSIRO Materials Science and Engineering, Victoria, Australia.
      • 2 Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia.

      Dextromethorphan was N-demethylated using the non-classical Polonovski reaction under continuous flow conditions, in two steps: initial N-oxidation with m-chloroperbenzoic acid followed by iron-catalysed N-demethylation of the resulting N-oxide.

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      A Two-Stage Continuous-Flow Synthesis of Spirooxazine Photochromic Dyes

      • Mark York123
      • Adriana Edenharter1
      • 1CSIRO Materials Science and Engineering, Clayton, Vic. 3169, Australia.
      • 2Cooperative Research Centre for Polymers, Notting Hill, Vic. 3168, Australia.
      • 3Advanced Polymerik Pty Ltd, Notting Hill, Vic. 3168, Australia.

      A continuous-flow process for the synthesis of several known and previously unreported spirooxazine photochromic dyes is reported. The process proceeds via an initial copper catalysed addition of substituted anilines to naphthalene-1,2-dione. This is followed by reaction with 1,3,3-trimethyl-2-methyleneindoline in the presence of hydroxylamine hydrochloride to give the desired spirooxazine products. The photochromic dyes were then cast into lenses to allow a preliminary evaluation of their properties.

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      Continuous Flow Synthesis of Organic Electronic Materials : Case Studies in Methodology Translation and Scale-up

      • Helga Seyler1
      • Stefan Haid2
      • Tae-Hyuk Kwon1
      • David J. Jones1
      • Peter Bäuerle2
      • Andrew B. Holmes1
      • Wallace W. H. Wong1*
      • 1Bio21 Institute, University of Melbourne, Australia.
      • 2Institute of Organic Chemistry II and Advanced Materials, University of Ulm, Germany.

      The continuous flow synthesis of functional thiophene derivatives was examined. Methodology for the lithiation of thiophene building blocks was developed using a commercial bench-top flow reactor. In addition, the advantages of flow processing were demonstrated in the synthesis of a high performance organic dye in gram scale.

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      Preparation of Arene Chromium Tricarbonyl Complexes Using Continuous-Flow Processing: (n6-C6H5CH3)Cr(CO)3 as an example

      • Christopher (Xiang) Lee1
      • Elizabeth A. Pedrick1
      • Nicholas E. Leadbeater1
      • 1Department of Chemistry, University of Connecticut, USA
      • 2Department of Community Medicine and Health Care, University of Connecticut Health Center, USA

      A continuous-flow approach to the direct synthesis of arene chromium tricarbonyl complexes is presented. By working in flow mode, it is possible to avoid some of the problems of batch synthesis, especially sublimation of the Cr(CO)6 starting material and the competitive decomposition of the product during the lengthy reaction times. Heating at 220 °C and operating with a residence time of 10 min through the heated zone allows for the synthesis of (η6-C6H5CH3)Cr(CO)3 as an example, along with a selection of other (arene)Cr(CO)3 complexes.

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      Visible Light-Initiated Preparation of Functionalized Polystyrene Monoliths for Flow Chemistry

      • Farhan R. Bou-Hamdan1
      • Kathleen Krüger1, Klaus Tauer1, Tyler McQuade1,3 , Peter H. Seeberger 1,2
      • 1Max Planck Institute of Colloids and Interfaces Potsdam, Germany.
      • 2Institute of Chemistry and Biochemistry, Freie Universität Berlin , Germany.
      • 3Department of Chemistry and Biochemistry, Florida State University, USA.

      Styrenic monoliths are produced using a novel visible light-initiated method. Monoliths with varying pore sizes are produced using 1-dodecanol and 1-dodecanol/THF mixtures and it was demonstrated that the more volatile i-PrOH can replace 1-dodecanol while still providing the same porogenic properties. In addition, the visible light-initiation protocol enables the facile incorporation of monomers that are incompatible with thermal or UV-initiated monolith formation methods. In particular, a reactive N-hydroxysuccinimidyl (NHS)-ester can be incorporated into the monolith and then subsequently used as an attachment point for a catalyst. Lastly, we demonstrate that the functionalized monolith supports acylation reactions well and that the loading of the catalyst impacts the reaction rate.

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      Integrated Continuous Processing and Flow Characterization of RAFT Polymerization in Tubular Flow Reactors

      • Christian H. Hornung
      • Xuan Nguyen
      • Geoff Dumsday
      • Simon Saubern*
      • CSIRO Materials Science and Engineering, Victoria. Australia

      Several unit operations are combined in series to form an integrated, continuous polymerization process; namely inline degassing of monomer stock solution prior to reaction, polymerization using the RAFT approach and precipitation after reaction to form a solid polymeric product. The polymerization is conducted at 70–80 °C with reaction times of 30–90 min in a stainless steel tubular flow reactor, yielding poly(acrylamide) at high conversion (typically >90%) and with a low polydispersity of 1.14–1.23. The axial dispersion occurring inside the tubular flow reactor during polymerization is characterized by reaction profiling using a series of NMR samples. The process can be scaled up to a total output of 1.36 kg of polymer per day on this laboratory-scale reactor.

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      Synthesis of an H3 Antagonist via Sequential One-Pot Additions of a Magnesium Ate Complex and an Amine to a 1,4-Ketoester followed by Carbonyl-Directed Fluoride Addition

      • Joel M. Hawkins
      • Pascal Dubé
      • Mark T. Maloney
      • Lulin Wei. Marcus Ewing
      • Stephen M. Chesnut
      • Joshua R. Denette
      • Brett M. Lillie
      • Rajappa Vaidyanathan
      • Pharmaceutical Sciences, Pfizer Inc., Groton, USA

      We describe the development of an efficient and scalable process for the preparation of fluorocyclobutane-containing H3 antagonist, 1. The synthesis was accomplished by the chemoselective addition of a magnesium ate complex and an amine to a 1,4-ketoester in a one-pot sequence, followed by a diastereoselective carbonyl-directed fluorination. The chemoselective addition of the magnesium ate complex to the ketoester benefited from tight stoichiometric control, short addition times, and lower reaction temperatures, and thus was amenable to rapid mixing and excellent heat transfer in a flow reactor.

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      A “Catch-React-Release” Method for the Flow Synthesis of 2-Aminopyrimidines and Preparation of the Imatinib Base

      • Richard J. Ingham
      • Elena Riva
      • Nikzad Nikbin
      • Ian R. Baxendale
      • Steven V. Ley*
      • Innovative Technology Centre, University of Cambridge, U.K.

      The development of a monolith-supported synthetic procedure is reported, taking advantage of flow processing and the superior flow characteristics of monolithic reagents over gel-phase beads, to allow facile access to an important family of 2-aminopyrimidine derivatives. The process has been successfully applied to a key precursor on route to Imatinib (Ar = 3-pyridyl, R1 = 2-methyl-5-nitrobenzyl, R2 = H).

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      Sustainable and efficient methodology for CLA synthesis and identification

      • Andres Moreno
      • Maria Moreno
      • Maria Victoria Gómez
      • Cristina Cebrian
      • Pilar Prieto
      • Antonio de la Hoz
      • Departamento de Química Inorgánica, , Universidad de Castilla-La Mancha, Ciudad Real, Spain.

      Microwave-assisted organic synthesis and continuous-flow techniques have been successfully employed for the preparation of conjugated linoleic acids (CLA), compounds with high health beneficial effects. A good production rate of CLA was obtained. A sustainable methodology for the differentiation of both positional and geometrical CLA isomers (diene), based on the analysis by NMR spectroscopy of the resulting Diels–Alder cycloadducts with an appropriate dienophile, was developed.

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      A Continuous Flow Process for the Radical Induced End Group Removal of RAFT Polymers

      • Christian H. Hornung
      • Almar Postma
      • Simon Saubern
      • John Chiefari
      • CSIRO Materials Science & Engineering, Victoria Australia

      A continuous flow process for the radical-induced end-group removal of polymers made by a RAFT process is described. A series of different monomers, including acrylamides, methacrylate, and styrene are polymerized at 70–100 °C using various different RAFT agents, solvents, and radical initiators. The subsequent end group removal process is carried out in a steel tube flow reactor system at 100 °C in organic solvents or water. After reaction, the polymers exhibit low polydispersities between 1.03 and 1.19, and average molecular weights between 7500 and 22 800 g · mol−1. This continuous flow approach provides a facile alternative scale-up route to conventional batch operation and can be integrated into a sequential flow process consisting of RAFT polymerization followed by post-treatment.

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      Continuous Synthesis and Purification by Direct Coupling of a Flow Reactor with Simulated Moving-Bed Chromatography

      • Alexander G. O’Brien1
      • Zoltán Horváth3
      • François Lévesque1
      • Ju Weon Lee3
      • Andreas Seidel-Morgenstern3
      • Peter H. Seeberger1,2
      • 1Department for Biomolecular Systems, Max-Planck Institute for Colloids and Interfaces, Potsdam, Germany
      • 2Freie Universität Berlin, Germany
      • 3Max-Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany

      Continuous synthesis meets continuous purification to produce pure products from crude reaction mixtures. In the nucleophilic aromatic substitution of 2,4-difluoronitrobenzene with morpholine the desired monosubstituted product can be continuously separated from the byproducts in a purity of over 99 % by coupling a flow reactor to a simulated moving bed (SMB) chromatography module (see scheme).

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      Asymmetric Homogeneous Hydrogenation in Flow using a Tube-in-Tube Reactor

      Sean Newton1, Steven V. Ley1, Eva Casas Arcé2, Damian M. Grainger2

      • 1Department of Chemistry, University of Cambridge, U.K.
      • 2Johnson Matthey Catalysis and Chiral Technology, Cambridge, U.K.

      In this update, the asymmetric homogeneous hydrogenation of a number of trisubstituted olefins utilizing the recently developed tube-in-tube gas-liquid flow reactor is described. A number of chiral iridium- and rhodium-based catalysts and other parameters such as pressure, solvent, temperature and catalyst loading were screened. The advantage of the flow set-up for rapid screening and optimization of reaction parameters is illustrated. Furthermore, a comparative study using batch conditions aided in the optimization of the flow reaction set-up. The set-up was further modified to recycle the catalyst which prolonged catalytic activity.

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      Continuous Flow Synthesis of Secondary Amides by Tandem Azidation- Amidation of Anilines

      • Christian Spiteri
      • John E. Moses*
      • School of Chemistry, University of Nottingham, UK

      The continuous flow synthesis of a variety of secondary amides by tandem azidation–amidation of anilines is described. This new procedure benefits from the improved safety feature of generating aromatic azides in flow, thus ensuring low concentrations of any potentially hazardous intermediates. The protocol was amenable to the production of multi-gram quantities of the amide product.

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      Continuous Flow Hydrogenation Using an On-Demand Gas Delivery Reactor

      • Michael A. Mercadante
      • Christopher B. Kelly
      • Christopher (Xiang) Lee
      • Nicholas E. Leadbeater*
      • Department of Chemistry, University of Connecticut, USA

      A continuous-flow approach to the hydrogenation of alkenes utilizing Wilkinson’s catalyst is reported. The approach relies on a newly developed coil design in which it is possible to load gas and heat the reaction mixture simultaneously. The hydrogenation of various substrates has been performed successfully on small scale and can be scaled up substantially.

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      Continuous flow synthesis and scale-up of glycine- and taurine-conjugated bile salts

      • Francesco Venturoni
      • Antimo Gioiello
      • Roccaldo Sardella
      • Benedetto Natalini
      • Roberto Pellicciari
      • Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Italy

      A multi-gram scale protocol for the N-acyl amidation of bile acids with glycine and taurine has been successfully developed under continuous flow processing conditions. Selecting ursodeoxycholic acid (UDCA) as the model compound and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) as the condensing agent, a modular mesoreactor assisted flow set-up was employed to significantly speed up the optimization of the reaction conditions and the flow scale-up synthesis. The results in terms of yield, in line purification, analysis, and implemented flow set-up for the reaction optimization and large scale production are reported and discussed.

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      Phase-Transfer Catalysis under Continuous Flow Conditions: An Alternative Approach to the Biphasic Liquid/Liquid O-Alkylation of Phenols

      • Daniele De Zani2
      • Matteo Colombo1
      • 1NiKem Research 20021 via Zambeletti 25 Milan Baranzate Italy
      • 2Erregierre, San Paolo D'Argon Bergamo Italy

      O-Alkylation of phenol compounds was performed in a continuous flow apparatus under biphasic liquid/liquid conditions and promoted by tetrabutylammonium bromide (TBAB) as a phase-transfer catalyst. The segmented flow that is generated within the flow system is able to afford the desired ethers in high yield and in very short times.

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      An efficient method for the lipase-catalysed resolution and in-line purification of racemic flurbiprofen in a continuous-flow reactor

      • Lucia Tamborini1
      • Diego Romano2
      • Andrea Pinto1
      • Arianna Bertolani1,2
      • Francesco Molinari2
      • Paola Conti1
      • 1Dipartimento di Scienze Farmaceutiche ‘Pietro Pratesi’, Universitá degli Studi di Milano, Italy
      • 2Dipartimento di Scienze e Tecnologie Alimentari e Microbiologiche, Universitá degli Studi di Milano, Italy

      The lipase-catalysed kinetic resolution of flurbiprofen was performed in a flow-chemistry reactor allowing for a significant reduction of the reaction time compared to the classical batch method. The process was implemented by adding an in-line purification step of the exiting solution, consisting in a catch and release protocol, which allows easy separation and recovery of both (S)-flurbiprofen and (R)-flurbiprofen butyl ester with an enantiomeric excess ≥90% and a chemical purity >98%.

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      Development of a Continuous Flow Scale-Up Approach of Reflux Inhibitor AZD6906

      • Tomas Gustafsson
      • Henrik Sörensen
      • Fritiof Pontén*
      • Medicinal Chemistry, AstraZeneca R&D Mölndal, Sweden

      Early scale-up work of a promising reflux inhibitor AZD6906 is described. Two steps of an earlier route were adapted to be performed in continuous flow to avoid issues related to batch procedures, resulting in a robust method with reduced cost of goods and improved product quality. Toxic and reactive reagents and starting materials could be handled in a flow regime, thereby allowing safer and more convenient reaction optimization and production.

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      Soluble Polymer-Supported Flow Synthesis: A Green Process for the Preparation of Heterocycles

      Nicolò Prosa, Raphaël Turgis, Riccardo Piccardi, Marie-Christine Scherrmann

      • Institut de Chimie Moléculaire et des Matériaux d'Orsay, Université Paris-Sud, France

      PEG-supported aqueous flow synthesis coupled with ultrafiltration as the separation technique has been investigated for the first time. This strategy was applied to the preparation of new 3,4-dihydropyrimidin-2(1H)-ones, tetrazoles and tetrahydro-1,3-oxazines from the same PEG-linked aldehyde as case studies. Dihydropyrimidinones were prepared by a copper(II)-catalysed Biginelli reaction whereas a new tetrazole-containing compound was obtained by Baylis–Hillman reaction followed by reduction and 1,3-dipolar cycloaddition. Finally, various new tetrahydro-1,3-oxazines were prepared by a four-step synthesis, that is, Baylis–Hillman reaction, Michael addition of amines, cyclization with formaldehyde and hydrolysis of the linkage to PEG. The use of water during the synthesis and most of the purification steps, as well as the benefits of the flow process in terms of improved safety and heat transfer agree with the principles of green chemistry.

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      Scale-Up of Flow-Assisted Synthesis of C2-Symmetric Chiral PyBox Ligands

      Claudio Battilocchio1,3, Marcus Baumann1, Ian R. Baxendale1, Mariangela Biava3, Matthew O. Kitching1, Steven V. Ley1, Rainer E. Martin*2, Stephan A. Ohnmacht2, Nicholas D. C. Tappin1

      • 1Department of Chemistry, University of Cambridge, UK
      • 2F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Basel, Switzerland
      • 3Department of Pharmaceutical Chemistry and Technology, Sapienza University of Rome, Italy

      A series of PyBox ligands were prepared from commercially available chelidonic acid by a multistep flow sequence using mesoreactor technology. A chloro group introduced onto the ligand scaffold was subsequently exploited to give amine derivatives ready for immobilization through microencapsulation technologies.

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      Continuous-Flow Synthesis of the Anti-Malaria Drug Artemisinin

      • François Lévesque1
      • Peter H. Seeberger1,2
      • 1Department for Biomolecular Systems, Max-Planck Institute for Colloids and Interfaces, Germany
      • 2Institute for Chemistry and Biochemistry, Freie Universität Berlin, Germany

      Malaria is a serious global health issue. Artemisinin combination treatments are the first-line drugs, but supplies are limited because artemisinin is obtained solely by extraction from Artemisia annua. A continuous-flow process that converts dihydroartemisinic acid into artemisinin (see scheme) was shown to be an inexpensive and scalable process that can ensure a steady, affordable supply of artemisinin.

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      The Continuous-Flow Synthesis of Carboxylic Acids using CO2 in a Tube-In-Tube Gas Permeable Membrane Reactor

      • Anastasios Polyzos
      • Matthew O’Brien
      • Trine P. Petersen
      • Ian R. Baxendale
      • Steven V. Ley
      • Innovative Technology Centre, Department of Chemistry, University of Cambridge

      Keep it simple: A gas–liquid flow reactor has been developed based on a gas permeable tube-in-tube configuration which effectively delivers gas to a liquid substrate stream in a safe, continuous fashion. A series of carboxylic acids were prepared from the reaction of CO2 with a range of Grignard reagents (see picture).

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      Continuous proline catalysis via leaching of solid proline

      • Suzanne M. Opalka1
      • Ashley R. Longstreet2
      • D. Tyler McQuade2
      • 1Department of Chemistry and Chemical Biology, Cornell University, USA
      • 2Department of Chemistry and Biochemistry, Florida State University,USA

      Herein, we demonstrate that a homogeneous catalyst can be prepared continuously via reaction with a packed-bed of a catalyst precursor. Specifically, we perform continuous proline catalyzed α-aminoxylations using a packed-bed of L-proline. The system relies on a multistep sequence in which an aldehyde and thiourea additive are passed through a column of solid proline, presumably forming a soluble oxazolidinone intermediate. This transports a catalytic amount of proline from the packed-bed into the reactor coil for subsequent combination with a solution of nitrosobenzene, affording the desired optically active α-aminooxy alcohol after reduction. To our knowledge, this is the first example in which a homogeneous catalyst is produced continuously using a packed-bed. We predict that the method will not only be useful for other L-proline catalyzed reactions, but we also foresee that it could be used to produce other catalytic species in flow.

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

      • Kimberley A. Roper1
      • Heiko Lange1
      • Anastasios Polyzos1
      • Malcolm B. Berry2
      • Ian R. Baxendale1
      • Steven V. Ley1
      • 1Innovative Technology Centre, University of Cambridge
      • 2GlaxoSmithKline, Stevenage, UK

      Herein we describe the application of a monolithic triphenylphosphine reagent to the Appel reaction in flow-chemistry processing, to generate various brominated products with high purity and in excellent yields, and with no requirement for further off-line purification.Herein we describe the application of a monolithic triphenylphosphine reagent to the Appel reaction in flow-chemistry processing, to generate various brominated products with high purity and in excellent yields, and with no requirement for further off-line purification.

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      Application of Flow Chemistry to the Selective Reduction of Esters to Aldehydes

      Juan de M. Muñoz1, Jesús Alcázar1, Antonio de la Hoz2, Angel Díaz-Ortiz2

      • 1Janssen, Toledo, Spain
      • 2Facultad de Ciencias Químicas, Universidad de Castilla-La Mancha, Spain

      The reduction of esters to aldehydes is an important transformation in organic chemistry and several reducing agents have been described. However, the use of this reaction in medicinal and natural product chemistry is limited due to the instability of the intermediates and the high reactivity of the reaction products. In the current article, the general and selective reduction of esters with diisobutyl-tert-butoxyaluminum hydride in flow is reported. This reagent allows esters to be reduced in the presence of different functional groups, including those considered to be of similar or higher reactivity.

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      Synthesis of Annulated Pyridines by Intramolecular Inverse-Electron-Demand Hetero-Diels-Alder Reaction under Superheated Continuous Flow Conditions

      Rainer E. Martin1, Falk Morawitz1, Christoph Kuratli1, André M. Alker2, Alexander I. Alanine1

      • 1Chemistry Technology and Innovation, F. Hoffmann-La Roche Ltd, Basel, Switzerland
      • 2Biostructure Section, F. Hoffmann-La Roche Ltd,Basel, Switzerland

      Pyrimidine alkynes can be transformed into the corresponding annulated pyridines efficiently in flow. The superheating of organic solvents far beyond their boiling point enables toxic and difficult to workup solvents such as nitrobenzene or chlorobenzene, which are usually employed for these reactions, to be replaced by less harmful ones like toluene. The relative rate of reactivity for a series of structurally close starting materials was investigated and a scalable flow process was developed, providing facile access to a series of novel annulated pyridine building blocks. The effect of thermal volume expansion of solvents under superheated conditions was found to be significant and influenced the residence times considerably. To obtain meaningful and accurate residence times, flow rates need to be corrected for volume expansion. To avoid confusion with residence times, tR, calculated from nominal flow rates, we would propose to use for such corrected residence times the term effective residence time, tR,eff.

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      Continuous Preparation of Arylmagnesium Reagents in Flow with Inline IR Monitoring

      • Tobias Brodmann1
      • Peter Koos1
      • Albrecht Metzger1
      • Paul Knochel*2
      • Steven V. Ley*1
      • 1Department of Chemistry, University of Cambridge, U.K.
      • 2Department of Chemistry, Ludwig Maximilians-Universität München, Germany

      A newly developed microscale ReactIR flow cell was used as a convenient and versatile inline analytical tool for Grignard formation in continuous flow chemical processing. The LiCl-mediated halogen/Mg exchange reaction was used for the preparation of functionalized arylmagnesium compounds from aryl iodides or bromides. Furthermore, inline IR monitoring was used for the analysis of conversion and possible byproduct formation, as well as a potential tool for elucidation of mechanistic details. The results described herein indicate that the continuous flow systems are effective for highly exothermic reactions such as the Grignard exchange reaction due to fast mixing and efficient heat transfer.

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      Lead Diversification 2: Application to P38, gMTP and lead compounds

      • M. Abid Masood1
      • Marc Bazin2
      • Mark E. Bunnage1
      • Andrew Calabrese3
      • Mark Cox1
      • Sally-Ann Fancy1
      • Elizabeth Farrant1
      • David W. Pearce1
      • Manuel Perez1
      • Laure Hitzel1
      • Torren Peakman1
      • 1Worldwide Medicinal Chemistry, Pfizer, UK
      • 2Hepatochem, Cambridge, MA, USA
      • 3Celgene San Diego, USA

      Lead Diversification is a new technology platform developed at Pfizer for the functionalization of drug molecules using C–H activation. We describe its application to some drug programs such as P38 and gMTP and the development of some new plate based screens including a fluorination screen.

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      New Insights into Cyclobutenone Rearrangements: A Total Synthesis of the Natural ROS-Generating Anti-Cancer Agent Cribrostatin 6†

      Mubina Mohamed1, Théo P. Gonçalves1, Prof. Richard J. Whitby1, Dr. Helen F. Sneddon2, Prof. David C. Harrowven1

      • 1 Chemistry, University of Southampton, UK
      • 2 GlaxoSmithKline Medicines Research Centre, UK

      Aryl- and heteroarylcyclobutenone rearrangements proceed in excellent yield under continuous-flow conditions. The former shows a Hammett correlation with σI providing strong evidence that electrocyclisation is the rate-determining step and has a late transition state. The reaction has been modelled by using DFT and CCSD(T) methods, with the latter giving excellent correlation with the experimental rate constant. A short and efficient total synthesis of cribrostatin 6, an anti-neoplastic and anti-microbial agent, provides a topical demonstration of the value of this method.

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      New Insights into Cyclobutenone Rearrangements: A Total Synthesis of the Natural ROS-Generating Anti-Cancer Agent Cribrostatin (ROS=reactive-oxygen species)

      Mubina Mohamed1, Théo P. Gonçalves1, Richard J. Whitby1, Helen F. Sneddon2, David C. Harrowven1

      • 1Dept of Chemistry, University of Southampton, UK
      • 2GSK Medicines Research Centre, Stevenage, UK

      Aryl- and heteroarylcyclobutenone rearrangements proceed in excellent yield under continuous-flow conditions. The former shows a Hammett correlation with σI providing strong evidence that electrocyclisation is the rate-determining step and has a late transition state. The reaction has been modelled by using DFT and CCSD(T) methods, with the latter giving excellent correlation with the experimental rate constant. A short and efficient total synthesis of cribrostatin 6, an anti-neoplastic and anti-microbial agent, provides a topical demonstration of the value of this method.

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      A continuous-flow synthesis of annulated and polysubstituted furans from the reaction of ketones and a-haloketones

      • Mark York
      • CSIRO Materials Science and Engineering, Australia
      • Cooperative Research Centre for Polymers, Notting Hill, Australia

      A synthesis of di-, tri- and tetra-substituted furans from reaction of the corresponding ketones and α-haloketones with LiHMDS is reported. Reaction under continuous-flow conditions gave increased yields and removed the need for external cooling when compared to the unoptimised batch conditions.

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      The Oxygen-Mediated Synthesis of 1,3-Butadiynes in Continuous Flow: Using Teflon AF-2400 to Effect Gas/Liquid Contact

      • Trine P. Petersen1,2,3
      • Anastasios Polyzos1,4
      • Matthew O’Brien1
      • Trond Ulven2
      • Ian R. Baxendale1
      • Steven V. Ley1
      • 1Whiffen Laboratory, University of Cambridge, UK
      • 2Department of Physics and Chemistry, University of Southern Denmark
      • 3Discovery Chemistry and DMPK, H. Lundbeck A/S,Denmark
      • 4CSIRO, Materials Science and Engineering, Australia

      The gas is always greener: A continuous flow Glaser–Hay coupling reaction system, mediated by molecular oxygen, is developed based on a tube-in-tube gas/liquid reactor/injector. The system uses a semi-permeable Teflon AF-2400 membrane to effect rapid gas/liquid contact in flow, affording homogeneous solutions of oxygen. Measurements of out-gassing downstream of the back-pressure regulator indicate the onset of saturation is reached after about 16 seconds.

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      Continuous flow synthesis of conjugated polymers

      • Helga Seyler
      • David J. Jones
      • Andrew B. Holmes
      • Wallace W. H. Wong
      • Bio21 Institute, University of Melbourne, Australia

      A selection of conjugated polymers, widely studied in organic electronics, was synthesised using continuous flow methodology. As a result of superior heat transfer and reagent control, excellent polymer molecular mass distributions were achieved in significantly reduced reaction times compared to conventional batch reactions.

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      Suzuki-Miyaura Cross-Coupling of Heteroaryl Halides and Arylboronic Acids in Continuous Flow

      • Timothy Noël
      • Andrew J. Musacchio
      • Department of Chemistry, MIT, USA

      General continuous-flow conditions for the Suzuki–Miyaura cross-coupling of heteroaryl halides and (hetero)arylboronic acids have been developed. A wide range of heterobiaryl products is obtained in excellent yields (20 examples) employing low catalyst loadings (0.05–1.5 mol % Pd).

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      Nitrile Oxide 1,3-Dipolar Cycloaddition by Dehydration of Nitromethane Derivatives Under Continuous Flow Conditions

      • Malte Brasholz
      • Simon Saubern*
      • G. Paul Savage
      • CSIRO Materials Science and Engineering, Victoria, Australia.

      Aliphatic nitrile oxides were generated in situ, by dehydration of terminal nitro compounds, and reacted with dipolarophiles using continuous flow techniques to afford substituted isoxazolines. The yields of cycloadducts were comparable with traditional flask-based reactions but reaction times were much shorter. In-line scavenger cartridges conveniently removed by-products and unreacted reagents to give almost pure crude products. The process was demonstrated up to gram scale.

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      Continuous-flow, palladium-catalysed alkoxycarbonylation reactions using a prototype reactor in which it is possible to load gas and heat simultaneously

      • Michael A. Mercadante
      • Nicholas E. Leadbeater
      • Department of Chemistry, University of Connecticut, USA

      A prototype tube-in-tube reactor in which it is possible to load gas and heat simultaneously has been used in a continuous-flow approach to alkoxycarbonylation reactions of aryl iodides. In the stainless steel coil, liquid flows on the outside of a gas-permeable membrane. The coil can be heated and the temperature can be measured accurately via a probe touching the outer steel surface. A range of aryl iodides can be transformed to the corresponding esters in excellent conversion by reaction at 120 °C using 0.5 mol% palladium acetate as the catalyst with no additional ligand required. Small-scale optimization and substrate screening runs were followed by scale-up.

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

      • Farhan R. Bou-Hamdan
      • François Lévesque
      • Alexander G. O'Brien
      • Peter H. Seeberger
      • Max Planck Institute of Colloids and Interfaces, Berlin, Germany

      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.

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      Teflon AF-2400 mediated gas–liquid contact in continuous flow methoxycarbonylations and in-line FTIR measurement of CO concentration

      • Peter Koos
      • Ulrike Gross
      • Anastasios Polyzos
      • Matthew O'Brien
      • Ian Baxendale
      • Steven V. Ley
      • Innovative Technology Centre, University of Cambridge, UK

      We report on the development of a continuous flow process for the palladium catalysed methoxycarbonylation of aryl, heteroaromatic and vinyl iodides and an aryl bromide using a Teflon AF-2400 based Tube-in-Tube reactor to mediate the selective permeation of carbon monoxide into solution at elevated pressures. The low volume of pressurised gas within the reactor (5.6 mL) offers the potential for an enhanced safety profile compared to batch processes. We also present preliminary results for the use of in situFTIR to measure solution concentrations of carbon monoxide and demonstrate the use of a second reactor to effect the removal of carbon monoxide from the flow stream.

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      Rapid Access to α-Alkoxy and α-Amino Acid Derivatives through Safe Continuous-Flow Generation of Diazoesters

      • Hannah E. Bartrum1
      • David C. Blakemore2
      • Christopher J. Moody1
      • Christopher J. Hayes1
      • 1School of Chemistry, University of Nottingham, UK
      • 2Pfizer Global Research and Development, Sandwich, UK

      Microreactors: A highly efficient continuous-flow process has been developed for the synthesis of diazoesters from arylsulfonylhydrazones by means of in-flow Bamford–Stevens reactions. Furthermore, a range of α-alkoxy and α-amino acid derivatives have been prepared in excellent yields through rhodium(II)-mediated O[BOND]H and N[BOND]H insertions, without the need to isolate or handle the potentially hazardous diazo species (see scheme).

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      Ozonolysis in Flow Using Capillary Reactors

      • M. D. Roydhouse1
      • A. Ghaini2
      • A. Constantinou
      • A. Cantu-Perez2
      • W. B. Motherwell1
      • A. Gavriilidis2
      • 1 Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ
      • 2 Department of Chemical Engineering, University College London, Torrington Place, London WC1E 7JE
      Ozonolysis in flow using capillary reactor

      Reactions of n-decene with ozone and subsequent quenching of the formed ozonides were carried out under flow conditions using the standard Vapourtec flow system equipped with a cooled flow cell. The reactions were performed continuously and in the annular flow regime within the circular cross-section channels. Typical flow rates were 0.25–1 mL min–1 for liquid and 25–100 mL min–1 for gas, reactor volumes were 0.07–10 mL formed of 1 mm ID PFA tubing. The reaction temperature was −10 °C. The flow was not always smooth, while waves in the liquid film and droplets in the gas core were observed. Liquid residence times were found to be independent of gas flow rates and increasing with decreasing liquid flow rates. Substrate residence times in the ozonolysis reactor ranged between 1 and 80 s, and complete conversion could be achieved at ∼1 s residence time. Two common reductants, triethylphosphite and triphenylphosphine, were examined as to their suitability under flow conditions. Triphenylphosphine achieved faster reduction of the intermediate ozonides, resulting in a greater than 10:1 selectivity for the aldehyde over the corresponding acid. The cooling system provided a safe and efficient control of the highly exothermic reaction system. The configuration of the system allowed the production of chemically significant amounts (1.8 g h–1 at 1.3 ozone equivalents), with minimal amounts of ozonides present at any time.

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      An Integrated Flow and Batch-Based Approach for the Synthesis of O-Methyl Siphonazole

      • Marcus Baumann
      • Ian R. Baxendale
      • Malte Brasholz
      • John J. Hayward
      • Steven V. Ley
      • Nikzad Nikbin
      • Innovative Technology Centre, Cambridge, UK

      The bisoxazole containing natural product O-methyl siphonazole was assembled using a suite of microreactors via a flow-based approach in concert with traditional batch methods. The use of a toolbox of solid-supported scavengers and reagents to aid purification afforded the natural product in a total of nine steps.

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      Synthesis of a Drug-Like Focused Library of Trisubstituted Pyrrolidines Using Integrated Flow Chemistry and Batch Methods

      • Marcus Baumann1
      • Ian R. Baxendale1
      • Steven V. Ley1
      • Christoph Kuratli2
      • Rainer E. Martin2
      • Josef Schneider2
      • 1Innovative Technology Centre, University of Cambridge, U.K.
      • 2F. Hoffmann-La Roche Ltd., Basel, Switzerland

      A combination of flow and batch chemistries has been successfully applied to the assembly of a series of trisubstituted drug-like pyrrolidines. This study demonstrates the efficient preparation of a focused library of these pharmaceutically important structures using microreactor technologies, as well as classical parallel synthesis techniques, and thus exemplifies the impact of integrating innovative enabling tools within the drug discovery process.

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      Nitration Chemistry in Continuous Flow using Fuming Nitric Acid in a Commercially Available Flow Reactor

      • Cara E. Brocklehurst
      • Hansjoerg Lehmann
      • Luigi La Vecchia
      • Global Discovery Chemistry, Novartis, Basel, Switzerland

      The paper will describe the use of flow chemistry for scaling up exothermic or hazardous nitration reactions. Such reactions often cause time delays to the delivery of larger batches of intermediates or final compounds for medicinal chemistry projects, because considerable time is required for safety evaluation and, if necessary, modification of the procedure so that it can be scaled-up and run in a safe manner. A commercially available continuous flow reactor was used in the scale up of three challenging nitrations including a reaction involving a potentially explosive mixture of acetic acid and fuming nitric acid, with a productivity of 97 g/h.

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      Synthesis of (+)-Dumetorine and Congeners by Using Flow Chemistry Technologies

      Elena Riva2, Anna Rencurosi1, Stefania Gagliardi1, Daniele Passarella2, Marisa Martinelli1*

      • 1NiKem Research S.r.l., Milan, Italy
      • 2Università degli Studi di Milano,Milan, Italy

      An efficient total synthesis of the natural alkaloid (+)-dumetorine by using flow technology is described. The process entailed five separate steps starting from the enantiopure (S)-2- (piperidin-2-yl)ethanol 4 with 29 % overall yield. Most of the reactions were carried out by exploiting solvent superheating and by using packed columns of immobilized reagents or scavengers to minimize handling. New protocols for performing classical reactions under continuous flow are disclosed: the ring-closing metathesis reaction with a novel polyethylene glycol-supported Hoveyda catalyst and the unprecedented flow deprotection/Eschweiler–Clarke methylation sequence. The new protocols developed for the synthesis of (+)-dumetorine were applied to the synthesis of its simplified natural congeners (−)-sedamine and (+)-sedridine.

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      Continuous flow synthesis of fullerene derivatives

      • Helga Seyler
      • Wallace Wing Ho Wong
      • Dave Jones
      • Andrew B. Holmes
      • University Of Melbourne, Australia

      Various fullerene-based electron acceptor materials for organic photovoltaic applications were prepared via [3 + 2] and [4 + 2] cycloadditions using a continuous flow approach. The 1,3-dipolar cycloaddition of the tosylhydrazone precursor and the Diels−Alder cycloaddition of indene to either C60 or C70 under conventional batch reaction conditions were translated to the continuous flow process. By varying the residence time, temperature, and equivalents of cycloaddition reagent, significant improvements in yields and reaction times were achieved over conventional batch processes.

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      Preparation of fluoxetine by multiple flow processing steps

      • Batoul Ahmed-Omer
      • Adam J. Sanderson
      • Eli Lilly and Co. Ltd.
      • Lilly Research Centre, UK.

      Microflow technology is established as a modern and fashionable tool in synthetic organic chemistry, bringing great improvement and potential, on account of a series of advantages over flask methods. The study presented here focuses on the application of flow chemistry process in performing an efficient multiple step syntheses of (±)-fluoxetine as an alternative to conventional synthetic methods, and one of the few examples of total synthesis accomplished by flow technique.

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      Oxidation Reactions in Segmented and Continuous Flow Chemical Processing Using an N-(tert-Butyl)phenylsulfinimidoyl Chloride Monolith

      • Heiko Lange
      • Matthew J. Capener
      • Alexander X. Jones
      • Catherine J. Smith
      • Nikzad Nikbin
      • Ian R. Baxendale
      • Steven V. Ley*
      • Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK

      A supported version of N-(tert-butyl)phenylsulfinim­idoyl chloride on a monolithic material is described, which can be incorporated into a flow chemical processing arrangement to oxidise a variety of substrates in both stoichiometric and catalytic processes to yield products in high yields and in high purity after in-line workup.

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      Highly efficient dehydration of carbohydrates to 5-(chloromethyl)furfural (CMF), 5-(hydroxymethyl)furfural (HMF) and levulinic acid by biphasic continuous flow processing

      • Malte Brasholz
      • Karin von Känel
      • Christian H. Hornung
      • Simon Saubern
      • John Tsanaktsidis
      • CSIRO Materials Science & Engineering, Victoria , Australia

      Using a continuous flow reactor, the dehydration of D-fructose and other carbohydrates to 5-(chloromethyl)furfural (1) is achieved in reaction times as short as 60 s. The biphasic flow process allows for high-yielding multigram scale production of CMF (1) which is obtained with excellent purity after a simple extractive work-up. Efficient conversion of D-fructose into 5-(hydroxymethyl)furfural (2) and levulinic acid (6) is also demonstrated using flow reactor techniques.

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      A General, One-Step Synthesis of Substituted Indazoles using a Flow Reactor

      • Rob C. Wheeler
      • Emma Baxter
      • Ian B. Campbell
      • Simon J. F. Macdonald
      • GlaxoSmithKline, Stevenage, UK

      Flow chemistry is a rapidly emerging technology within the pharmaceutical industry, both within medicinal and development chemistry groups. The advantages of flow chemistry, increased safety, improved reproducibility, enhanced scalability, are readily apparent, and we aimed to exploit this technology in order to provide small amounts of pharmaceutically interesting fragments via a safe and scalable route, which would enable the rapid synthesis of multigram quantities on demand. Here we report a general and versatile route which utilises flow chemistry to deliver a range of known and novel indazoles, including 3-amino and 3-hydroxy analogues.

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      Controlled RAFT Polymerization in a Continuous Flow Microreactor

      • Christian H. Hornung
      • Carlos Guerrero-Sanchez
      • Malte Brasholz
      • Simon Saubern
      • John Chiefari
      • Graeme Moad
      • Ezio Rizzardo
      • San H. Thang
      • CSIRO Materials Science & Engineering, Victoria, Australia

      Controlled radical polymerization using the reversible addition−fragmentation chain transfer approach (RAFT) was successfully conducted under continuous flow processing conditions, provided that steel tubing was used to prevent quenching of the radical process by oxygen. A series of different monomers, including acrylamides, acrylates, and vinyl acetate, were polymerized to high conversions (between 80 and 100%) at temperatures between 70 and 100 °C using various initiators, solvents, and RAFT agents. Low dispersities, typically between 1.15−1.20, and average molecular weights similar to those of batch RAFT polymerizations were obtained. The methodology provides a facile, alternative scale-up route to conventional batch polymerization, which can be challenging because of the oxygen-sensitive nature of the RAFT process.

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      Diastereoselective Chain-Elongation Reactions Using Microreactors for Applications in Complex Molecule Assembly

      Catherine F. Carter1, Heiko Lange1, Daiki Sakai2, Ian R. Baxendale1, Steven V. Ley1

      • 1Innovative Technology Centre, University of Cambridge, UK, CB2 1EW, UK
      • 2Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan

      Diastereoselective chain-elongation reactions are important transformations for the assembly of complex molecular structures, such as those present in polyketide natural products. Here we report new methods for performing crotylation reactions and homopropargylation reactions by using newly developed low-temperature flow-chemistry technology. In-line purification protocols are described, as well as the application of the crotylation protocol in an automated multi-step sequence.

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      Decarboxylative biaryl synthesis in a continuous flow reactor

      • 1Paul P. Lange
      • 1Lukas J. Gooßen
      • 2Philip Podmore
      • 2Toby Underwood
      • 2Nunzio Sciammetta
      • 1Technische Universität Kaiserslautern, Germany
      • 2Pfizer Global R&D, Sandwich, UK

      A practical protocol was developed that allows performing decarboxylative cross-coupling reactions in continuous flow reactors. Various biaryls were thus synthesized from aromatic carboxylic acids and aryl triflates using a Cu/Pd-catalyst system.

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      A fully automated, multistep flow synthesis of 5-amino-4-cyano-1,2,3-triazoles

      • Catherine J. Smith
      • Nikzad Nikbin
      • Steven V. Ley
      • Heiko Lange
      • Ian R. Baxendale
      • Innovative Technology Centre, Cambridge, UK

      Having demonstrated in the preceding publication the flow synthesis of aryl azides, we describe here a general protocol for the in-line purification of these versatile intermediates. As part of this investigation, we evaluated the use of ReactIR 45m as a tool for real-time detection of hazardous azide contaminants. This azide synthesis and purification process was then incorporated into a multistep flow sequence to generate a small collection of 5-amino-4-cyano-1,2,3-triazoles directly from aniline starting materials in a fully automated fashion.

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      A breakthrough method for the accurate addition of reagents in multi-step segmented flow processing

      • Heiko Lange1
      • Catherine F. Carter1
      • Mark D. Hopkin1
      • Adrian Burke2
      • Jon G. Goode2
      • Ian R. Baxendale1
      • Steven V. Ley1
      • 1Innovative Technology Centre, University of Cambridge, UK
      • 2Mettler-Toledo AutoChem UK

      In order to use segmented chemical flow processing in more complex reaction sequences, a method has been developed to precisely control the addition of reagent streams during multi-step operations. Using in-line infra-red monitoring with a new LabVIEW software application, it is possible to control additional pumps to dispense further reagents in real time based upon the concentration of reaction intermediates. This enables precise mixing with perfect timing thus greatly increasing product quality and enabling segmented chemical flow processing to be used in extended reaction sequences.

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      One-Flow, Multistep Synthesis of Nucleosides by Brønsted Acid-Catalyzed Glycosylation

      • Adam Sniady
      • Matthew W. Bedore
      • Timothy F. Jamison
      • Novartis Institutes for Biomedical Research Inc., Cambridge, USA MIT, Cambridge, USA

      Nukleoside im Fluss: Eine universelle, skalierbare Methode für die Brønsted-Säure-katalysierte Bildung von Nukleosiden wird beschrieben. Dank der hohen Reaktionstemperaturen, die das Durchflussformat ermöglicht, können milde Brønsted-Säuren wie Pyridiniumtriflate eingesetzt werden. Auch die mehrstufige Synthese von ungeschützten Nukleosiden in einer einzelnen Durchflussprozedur ist möglich (siehe Schema).

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      Continuous flow thermolysis of azidoacrylates for the synthesis of heterocycles and pharmaceutical intermediates

      • Alexander G. O'Brien
      • François Lévesque
      • Peter H. Seeberger
      • Max Planck Institute of Colloids and Interfaces, Potsdam, Germany

      An efficient, safe and scalable procedure for the continuous flow thermolysis of azidoacrylates to yield indoles has been developed and was applied to the synthesis of related heterocycles. The scalability of the process was demonstrated in the continuous flow synthesis of a precursor to the DAAO inhibitor 4H-furo[3,2-b]pyrrole-5-carboxylic acid.

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      Safe and Reliable Synthesis of Diazoketones and Quinoxalines in a Continuous Flow Reactor

      A flow method for the synthesis of aliphatic and aromatic diazoketones from acyl chloride precursors has been developed and used to prepare quinoxalines in a multistep sequence without isolation of the potentially explosive diazoketone. The protocol showcases an efficient in-line purification using supported scavengers with time-saving and safety benefits and in particular a reduction in the operator’s exposure to carcinogenic phenylenediamines.

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      Continuous Flow Coupling and Decarboxylation Reactions Promoted by Copper Tubing

      • Yun Zhang1
      • Timothy F. Jamison2
      • Sejal Patel1
      • Nello Mainolfi1
      • 1Novartis Institutes for Biomedical Research Inc., Cambridge, USA
      • 2MIT, Cambridge, USA

      A convenient and efficient flow method for Ullmann condensations, Sonogashira couplings, and decarboxylation reactions using a commercially available copper tube flow reactor (CTFR) is described. The heated CTFR effects these transformations without added metals (e.g., Pd), ligands, or reagents, and in greater than 90% yield in most cases examined.

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      Synthesis of β-Keto Esters In-Flow and Rapid Access to Substituted Pyrimidines

      Hannah E. Bartrum1, David C. Blakemore2, Christopher J. Moody1, Christopher J. Hayes1

      • 1School of Chemistry, University of Nottingham, UK
      • 2Pfizer Global Research and Development, Sandwich, UK

      We have developed an in-flow process for the synthesis of β-keto esters via the BF3·OEt2-catalyzed formal C−H insertion of ethyl diazoacetate into aldehydes. The β-keto esters were then condensed with a range of amidines to give a variety of 2,6-substituted pyrimidin-4-ols.

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      Synthesis of 3-Aryl/benzyl-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]isoxazole Derivatives: A Comparison between Conventional, Microwave-Assisted and Flow-Based Methodologies

      Sabrina Castellano1, Lucia Tamborini2, Monica Viviano1, Andrea Pinto2, Gianluca Sbardella1, Paola Conti2

      • 1Dipartimento di Scienze Farmaceutiche, Universit degli Studi di Salerno, Via Ponte Don Melillo, 84084 Fisciano, Italy
      • 2Dipartimento di Scienze Farmaceutiche “Pietro Pratesi”, Universit degli Studi di Milano , Italy

      Two modern synthetic technologies to perform 1,3-dipolar cycloaddition reactions were compared. This study puts in evidence the power of microwave-assisted and flow-based methodologies compared to the conventional one in terms of reaction time and yield, and demonstrates the potential of flow chemistry in terms of time, automation, and scaling up opportunities.

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      Preparation of arylsulfonyl chlorides by chlorosulfonylation of in situ generated diazonium salts using a continuous flow reactor

      • Laia Malet-Sanz
      • Julia Madrzak
      • Steven V.Ley
      • Ian R.Baxendale
      • Innovative Technology Centre, University of Cambridge

      A new flow procedure for the preparation of arylsulfonyl chlorides from aniline starting materials is described. The reaction conditions are mild, requiring no added acid and are amenable to continuous flow processing, in a safe, easily scalable and less labour intensive way than the corresponding batch method.

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      A Gram-Scale Batch and Flow Total Synthesis of Perhydrohistrionicotoxin

      • Dr. Malte Brasholz1
      • Dr. James M. Macdonald1
      • Dr. Simon Saubern1
      • Dr. John H. Ryan1
      • Prof. Dr. Andrew B. Holmes1,2
      • 1CSIRO Molecular and Health Technologies, Victoria, Australia
      • 2School of Chemistry, Bio 21 Institute, University of Melbourne, Victoria, Australia

      Biologically valuable histrionicotoxin spiropiperidine alkaloids are found in the Colombian poison arrow frog Dendrobates histrionicus (shown on the cover). In their Full Paper on page 11471 ff., J. H. Ryan et al. describe efforts to synthesize an unnatural analogue, perhydrohistrionicotoxin, by combining conventional with microreactor techniques. (Photograph of Dendrobates histrionicus by Mauricio Rivera. Design by Martin Kowalski.)

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      A Continuous Flow Process Using a Sequence of Microreactors with In-line IR Analysis for the Preparation of N,N-Diethyl-4-(3-fluorophenylpiperidin-4-ylidenemethyl)benzamide as a Potent and Highly Selective δ-Opioid Receptor Agonist

      Zizheng Qian, Ian R. Baxendale, Steven V. Ley

      • Innovative Technology Centre, University of Cambridge
      Image for Chemistry A European Journal

      This article describes the design, optimisation and development of a continuous flow synthesis of N,N-diethyl-4-(3-fluorophenylpiperidin-4-ylidenemethyl)benzamide, a potent δ-opioid receptor agonist developed by AstraZeneca. The process employs a sequence of flow-based microreactors, with integrated purification employing solid-supported reagents and in-line IR analytical protocols using a newly developed ReactIR flow cell. With this monitoring device, initiation of the fourth input flow stream can be precisely controlled during the synthesis.


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      Synthesis of Highly Substituted Nitropyrrolidines, Nitropyrrolizines and Nitropyrroles via Multicomponent-Multistep Sequences within a Flow Reactor

      • Marcus Baumann
      • Ian R. Baxendale
      • Andreas Kirschning
      • Steven V. Ley*
      • Jens Wegner
      • Department of Chemistry, University of Cambridge

      We expand upon recent results concerning dipolar cycloaddition reactions of unstabilized azomethine ylids with nitro alkenes to generate 3-nitropyrrolidines via a flow chemistry sequence. This new work describes the development of a three-component coupling reaction between glycine esters, aldehydes and nitro alkenes. In order to further demonstrate the utility of flow technology in concert with heterogeneous reagents and scavengers for complex reaction sequences an in-line oxidation resulting in the conversion of tetra-substituted pyrrolidines to their pyrrole congeners has been developed.

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      KMnO4-Mediated Oxidation as a Continuous Flow Process

      • Jorg Sedelmeier
      • Steven V. Ley
      • Ian R. Baxendale
      • Marcus Baumann
      • Innovative Technology Centre, University of Cambridge

      An efficient and easily scalable transformation of alcohols and aldehydes to carboxylic acids and nitroalkane derivatives to the corresponding carbonyls and carboxylic acids using permanganate as the oxidant within a continuous flow reactor is reported. Notably, the generation and downstream processing of MnO2 slurries was not found to cause any blocking of the reactor when ultrasound pulses were applied to the flow system.

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      Flow synthesis of tricyclic spiropiperidines as building blocks for the histrionicotoxin family of alkaloids

      A domino cyclization reaction of the bis-unsaturated ketone 3 with hydroxylamine proceeds with good yield and high stereoselectivity, in a flow reactor system. The tricyclic spiropiperidine products 5 and 2 obtained are valuable building blocks for the synthesis of analogues of the histrionicotoxin alkaloids.

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      Effect of phase transfer chemistry, segmented fluid flow, and sonication on the synthesis of cinnamic esters

      • Mauro Riccaboni
      • Elena La Porta
      • Andrea Martorana
      • Roberta Attanasio
      • Department of Medicinal Chemistry, NiKem Research Srl, Milan, Italy

      Wittig reaction under Phase Transfer conditions was performed in a flow reaction system. Different bases, aldehydes, phosphonium salts, and flow reaction parameters were investigated, in absence of a phase transfert catalyst. An improvement of the reaction outcome (yield and reaction time) was achieved through the immersion of the reactor into an ultrasound bath

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      Continuous Flow Palladium(II)-Catalyzed Oxidative Heck Reactions with Arylboronic Acids

      Luke R. Odell1, Jonas Lindh1, Tomas Gustafsson2, Mats Larhed1*

      • 1Organic Pharmaceutical Chemistry, Department of MedChem, Uppsala University, Sweden
      • 2AstraZeneca R&D Mölndal, Sweden

      Palladium(II)-catalyzed oxidative Heck reactions were investigated under continuous flow conditions. Selective, fast and convenient protocols for the coupling of arylboronic acids with electron-rich and electron-poor olefins were developed by using a commercially available flow reactor.

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      A flow-based synthesis of Imatinib: the API of Gleevec

      • Mark D. Hopkin
      • Ian R. Baxendale
      • Steven V. Ley
      • Innovative Technology Centre, Department of Chemistry, University of Cambridge

      A concise, flow-based synthesis of Imatinib, a compound used for the treatment of chronic myeloid leukaemia, is described whereby all steps are conducted in tubular flow coils or cartridges packed with reagents or scavengers to effect clean product formation. An in-line solvent switching procedure was developed enabling the procedure to be performed with limited manual handling of intermediates.

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      Reaction of Grignard reagents with carbonyl compounds under continuous flow conditions

      • E. Riva1
      • S. Gagliardi2
      • M. Martinelli2
      • D. Passarella1
      • D. Vigo2
      • A. Rencurosi2
      • 1Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, Milano, Italy
      • 2NiKem Research S.r.l., , Milan, Italy

      This contribution details how a continuous flow reactor was used to react carbonyl compounds with Grignard reagents at room temperature in an efficient and safe manner. Flow rate, residence time and temperature were optimized for the preparation of a small collection of secondary and tertiary alcohols. Excellent yields and general applicability were observed using the set-up protocol. The procedure was also applied for the preparation of Tramadol, an analgesic drug belonging to the opioid group. The developed conditions allowed the selective addition of Grignard reagents to aldehydes and ketones in the presence of a nitrile function.

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      The application of flow microreactors to the preparation of a family of casein kinase I inhibitors

      • Francesco Venturoni
      • Nikzad Nikbin
      • Steven V. Ley
      • Ian R. Baxendale
      • Innovative Technology Centre, Department of Chemistry, University of Cambridge

      In this article we demonstrate how a combination of enabling technologies such as flow synthesis, solid-supported reagents and scavenging resins utilised under fully automated software control can assist in typical medicinal chemistry programmes. In particular automated continuous flow methods have greatly assisted in the optimisation of reaction conditions and facilitated scale up operations involving hazardous chemical materials. Overall a collection of twenty diverse analogues of a casein kinase I inhibitor has been synthesised by changing three principle binding vectors.

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      A Flow Process Using Microreactors for the Preparation of a Quinolone Derivative as a Potent 5HT1B> Antagonist

      • Zizheng Qian
      • Ian R. Baxendale
      • Steven V. Ley
      • Innovative Technology Centre, Department of Chemistry, University of Cambridge

      This article describes the continuous flow synthesis of ­6-methoxy-8-(4-methyl-1,4-diazepan-1-yl)-N-(4-morpholinophen-yl)-4-oxo-1,4-dihydroquinoline-2-carboxamide, a potent 5HT1B antagonist developed by AstraZeneca.

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      ReactIR Flow Cell: A New Analytical Tool for Continuous Flow Chemical Processing

      • Catherine F. Carter1
      • Heiko Lange1
      • Steven V. Ley1
      • Ian R. Baxendale1
      • Brian Wittkamp2
      • Jon G. Goode3
      • Nigel L. Gaunt3
      • 1Innovative Technology Centre, Department of Chemistry, University of Cambridge
      • 2Mettler-Toledo AutoChem, USA
      • 3Mettler-Toledo AutoChem, UK

      A newly developed ReactIR flow cell is reported as a convenient and versatile inline analytical tool for continuous flow chemical processing. The flow cell, operated with ATR technology, is attached directly into a reaction flow stream using standard OmniFit (HPLC) connections and can be used in combination with both meso- and microscale flow chemistry equipment. The iC IR analysis software (version 4.0) enables the monitoring of reagent consumption and product formation, aiding the rapid optimisation of procedures. Short-lived reactive intermediates can also be observed in situ, giving further mechanistic insight into complex transformations.

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      A highly efficient flow reactor process for the synthesis of N-Boc-3,4-dehydro-l-proline methyl ester

      • Lucia Tamborini
      • Paola Conti
      • Andrea Pinto
      • Carlo De Micheli
      • Dipartimento di Scienze Farmaceutiche ‘Pietro Pratesi’,
      • Università degli Studi di Milano, Italy

      The multi-step preparation of N-Boc-3,4-dehydro-l-proline methyl ester using a modular flow reactor is reported. The use of immobilised reagents and scavengers in pre-packed glass tubes allows us to obtain the pure product in 87% overall yield, 97% purity, and >98% enantiomeric excess without any additional purification step. Our flow-based protocol enables the rapid multi-gram synthesis (about 9 g/12 h) of the desired product.

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      [3+2] Dipolar cycloadditions of an unstabilised azomethine ylide under continuous flow conditions

      • Mark Grafton
      • Andrew C. Mansfield
      • M. Jonathan
      • Pfizer Global Research and Development, Sandwich, UK

      The [3+2] dipolar cycloaddition reactions of the unstabilised azomethine ylide precursor benzyl(methoxymethyl)(trimethylsilylmethyl)amine with 12 electron-deficient alkenes in the presence of catalytic trifluoroacetic acid are examined under continuous flow conditions (20–100 °C, 10–60 min residence time). The more reactive and hazardous alkenes such as ethyl acrylate, N-methylmaleimide and (E)-2-nitrostyrene afford substituted N-benzylpyrrolidine products in 77–83% yields, whereas less reactive dipolarophiles such as (E)-crotononitrile and ethyl methacrylate give lower yields (59–63%). Under optimised conditions, the reaction with ethyl acrylate is scaled up to afford ethyl N-benzylpyrrolidine-3-carboxylate (30 g, 87%) in 1 h.

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      Multi-Step Synthesis by Using Modular Flow Reactors: The Preparation of YneOnes and Their Use in Heterocycle Synthesis

      • Ian R. Baxendale1
      • Søren C. Schou2
      • Jörg Sedelmeier1
      • Steven V. Ley1
      • 1ITC, Department of Chemistry, University of Cambridge
      • 2LEO Pharma, Medicinal Chemistry Research, Denmark

      Multi-step in flow: The palladium-catalysed acylation of terminal alkynes for the synthesis of yne[BOND]ones as well as their further transformation to various heterocycles in a continuous-flow mode is presented. Furthermore, an extension of the simple flow configuration that allows for easy batch splitting and the generation of a heterocyclic library is described (see scheme).

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      A safe and reliable procedure for the iododeamination of aromatic and heteroaromatic amines in a continuous flow reactor

      • Laia Malet-Sanz
      • Julia Madrzak
      • Rhian S. Holvey
      • Toby Underwood
      • Research Chemistry, Pfizer Global Research and Development, Sandwich, UK

      A method for the safe and reliable iododeamination of aromatic and heteroaromatic amines under copper-free conditions is described and its scope is evaluated.

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      Development of fluorination methods using continuous-flow microreactors

      • Marcus Baumann
      • Ian R. Baxendale
      • Laetitia J. Martin
      • Steven V. Ley
      • Innovative Technology Centre, Cambridge, UK

      The safe and reliable use of various fluorination methods including nucleophilic fluorination (DAST), trifluoromethylation (Ruppert’s reagent) and electrophilic fluorination (Selectfluor®) in a continuous-flow microreactor is reported. Special attention was given to the use of in-line scavenging procedures in order to obtain clean products without the need for further purification.

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      Multistep Synthesis Using Modular Flow Reactors: Bestmann-Ohira Reagent for the Formation of Alkynes and Triazoles

      • Ian R. Baxendale1
      • Steven V. Ley1
      • Andrew C. Mansfield2
      • Christopher D. Smith1
      • 1ITC, Department of Chemistry, University of Cambridge,
      • 2Pfizer Global R&D Research Centre, Sandwich, (UK)

      Multistep in flow: The Seyferth–Gilbert reagent 1 has been applied in a flow system to rapidly synthesize terminal alkynes. The system has been further applied to synthesize triazole 3 from alcohol 2 in a three-step oxidation/homologation/copper(I)-catalyzed azide–alkyne cycloaddition sequence without isolation of intermediates (see scheme).

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      Efficient Continuous Flow Synthesis of Hydroxamic Acids and Suberoylanilide Hydroxamic Acid Preparation

      • E. Riva1
      • S. Gagliardi2
      • Caterina Mazzoni2
      • M. Martinelli2
      • D. Passarella1
      • D. Vigo2
      • A. Rencurosi2
      • 1Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, Italy
      • 2NiKem Research S.r.l., Milan, Italy

      A continuous flow tubing reactor can be used to readily transform methyl or ethyl carboxylic esters into the corresponding hydroxamic acids. Flow rate, reactor volume, and temperature were optimized for the preparation of a small collection of hydroxamic acids. Synthetic advantages were identified as an increased reaction rate and higher product purity. This method was also successfully applied to the multistep preparation of suberoylanilide hydroxamic acid, a potent HDAC inhibitor used in anticancer therapy.

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      A Bifurcated Pathway to Thiazoles and Imidazoles Using a Modular Flow Microreactor

      Ian R. Baxendale, Steven V. Ley, Christopher D. Smith, Lucia Tamborini, Ana-Florina Voica

      • Innovative Technology Centre, Cambridge, UK

      A scalable method for the preparation of 4,5-disubstituted thiazoles and imidazoles as distinct regioisomeric products using a modular flow microreactor has been devised. The process makes use of microfluidic reaction chips and packed immobilized-reagent columns to effect bifurcation of the reaction pathway.

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      The Use of Diethylaminosulfur Trifluoride (DAST) for Fluorination in a Continuous-Flow Microreactor

      Baumann, Marcus, Baxendale, Ian R., Ley, Steven V.

      • Innovative Technology Centre, Cambridge, UK

      The convenient and safe use of diethylaminosulfur tri­fluoride as a fluorinating agent in a continuous-flow microreactor is described using an in-line purification method to obtain clean reaction products.

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      A modular flow reactor for performing Curtius rearrangements as a continuous flow process

      • Marcus Baumann1
      • Ian R. Baxendale1
      • Steven V. Ley1
      • Nikzad Nikbin1
      • Christopher D. Smith1
      • Jason P. Tierney2
      • 1Innovative Technology Centre, Department of Chemistry, University of Cambridge
      • 2Neurology Lead Discovery Chemistry, GlaxoSmithKline R and D, Harlow, UK

      The use of a mesofluidic flow reactor is described for performing Curtius rearrangement reactions of carboxylic acids in the presence of diphenylphosphoryl azide and trapping of the intermediate isocyanates with various nucleophiles.

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      Azide monoliths as convenient flow reactors for efficient Curtius rearrangement reactions

      • Marcus Baumann
      • Ian R. Baxendale
      • Steven V. Ley
      • Nikzad Nikbin
      • Christopher D. Smith
      • Innovative Technology Centre, Cambridge, UK

      The preparation and use of an azide-containing monolithic reactor is described for use in a flow chemistry device and in particular for conducting Curtius rearrangement reactions via acid chloride inputs.

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      A Microcapillary Flow Disc Reactor for Organic Synthesis

      • Christian H. Hornung1
      • Malcolm R. Mackley2
      • Ian R. Baxendale1
      • Steven V. Ley1
      • 1Department of Chemistry, University of Cambridge
      • 2Department of Chemical Engineering, University of Cambridge

      This paper reports proof of concept, development, and trials for a novel plastic microcapillary flow disc (MFD) reactor. The MFD was constructed from a flexible, plastic microcapillary film (MCF), comprising parallel capillary channels with diameters in the range of 80−250 μm. MCFs were wound into spirals and heat treated to form solid discs, which were then capable of carrying out continuous flow reactions at elevated temperatures and pressures and with a controlled residence time. Three reaction schemes were conducted in the system, namely the synthesis of oxazoles, the formation of an allyl-ether, and a Diels−Alder reaction. Reaction scales of up to four kilograms per day could be achieved. The potential benefits of the MFD technology are compared against those of other reactor geometries including both conventional lab-scale and other microscale devices.

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      Tagged phosphine reagents to assist reaction work-up by phase-switched scavenging using a modular flow reactor

      • Christopher D. Smith
      • Ian Baxendale
      • Geoffrey Tranmer
      • Marcus Baumann
      • Stephen Smith
      • Russell Lewthwaite
      • Steven V. Ley
      • Department of Chemistry, University of Cambridge, UK

      The use of three orthogonally tagged phosphine reagents to assist chemical work-up via phase-switch scavenging in conjunction with a modular flow reactor is described. These techniques (acidic, basic and Click chemistry) are used to prepare various amides and tri-substituted guanidines from in situ generated iminophosphoranes.

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      [3 + 2] Cycloaddition of acetylenes with azides to give 1,4-disubstituted 1,2,3-triazoles in a modular flow reactor

      • Christopher D. Smith1
      • Ian R. Baxendale1
      • Steve Lanners1
      • John J. Hayward1
      • Steven V. Ley1
      • Stephen C. Smith2
      • 1Innovative Technology Centre, University of Cambridge, UK
      • 2Syngenta, Jealots Hill International Research Centre, UK

      The cycloaddition of acetylenes with azides to give the corresponding 1,4-disubstituted 1,2,3-triazoles is reported using immobilised reagents and scavengers in pre-packed glass tubes in a modular flow reactor.

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      Continuous Flow Ligand-Free Heck Reactions Using Monolithic Pd [0] Nanoparticles

      • Nikzad Nikbin
      • Mark Ladlow
      • Steven V. Ley
      • Department of Chemistry, University of Cambridge, UK

      An automated reactor has been developed for performing ligand-free Heck reactions in continuous flow mode. The reactor utilises a monolithic reactor cartridge derivatised with Pd(0) nanoparticles in-line with a scavenging cartridge containing Quadrapure-TU to efficiently capture palladium residues and thereby afford Heck products directly in high purity.

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      Fully Automated Flow-Through Synthesis of Secondary Sulfonamides in a Binary Reactor System

      • Charlotte M. Griffiths-Jones
      • Mark D. Hopkin
      • Daniel Jönsson
      • Steven V. Ley
      • David J. Tapolczay
      • Emma Vickerstaffe
      • Mark Ladlow
      • GlaxoSmithKline Cambridge Technology Centre, Cambridge

      A fully automated flow-through process for the production of secondary sulfonamides is presented. Primary sulfonamides were monoalkylated using a two-step “catch and release” protocol to generate library products of high purity. The automated flow synthesis platform incorporates four independent reactor columns and is able to perform automated column regeneration. A 48-member sulfonamide library was prepared as two 24-member sublibraries, affording library compounds in good yields and high purities without the need for further column chromatographic purification.

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      Fully Automated Continuous Flow Synthesis of 4,5-Disubstituted Oxazoles

      • Marcus Baumann
      • Ian R. Baxendale
      • Steven V. Ley
      • Christoper D. Smith
      • Geoffrey K. Tranmer
      • Innovative Technology Center, University of Cambridge

      A multipurpose mesofluidic flow reactor capable of producing gram quantities of material has been developed as an automated synthesis platform for the rapid on-demand synthesis of key building blocks and small exploratory libraries. The reactor is configured to provide the maximum flexibility for screening of reaction parameters that incorporate on-chip mixing and columns of solid supported reagents to expedite the chemical syntheses.

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      A flow reactor process for the synthesis of peptides utilizing immobilized reagents, scavengers and catch and release protocols

      • Ian R. Baxendale
      • Steven V. Ley
      • Christopher D. Smith
      • Geoffrey K. Tranmer
      • Innovative Technology Centre, Cambridge, UK

      A general flow process for the multi-step assembly of peptides has been developed and this procedure has been used to successfully construct a series of Boc, Cbz and Fmoc N-protected dipeptides in excellent yields and purities, including an extension of the method to enable the preparation of a tripeptide derivative.

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      A flow process for the multi-step synthesis of the alkaloid natural product oxomaritidine: a new paradigm for molecular assembly

      Ian R. Baxendale, Jon Deeley, Charlotte M. Griffiths-Jones, Steven V. Ley, Steen Saaby, Geoffrey K. Tranmer

      • Innovative Technology Centre, University of Cambridge

      A flow process for the multi-step synthesis of the alkaloid natural product (±)-oxomaritidine is described, mediated through the use of microfluidic pumping systems that progress material through various packed columns containing immobilized reagents, catalysts, scavengers or catch and release agents; our route involves the combination of seven separate synthetic steps linked into one continuous sequence utilizing flow chemistry.

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