Coupling reactions

    Coupling reactions are chemical reactions in which two chemical compounds are joined together to form a new compound. This type of reaction is commonly used in organic chemistry to synthesize complex molecules from simpler starting materials. For example, the reaction between an alkyl halide and a Grignard reagent can be used to form a carbon-carbon bond, which is the basis of many coupling reactions.

    Examples of published literature for Coupling reactions

    Photon Equivalents as a Parameter for Scaling Photoredox Reactions in Flow: Translation of Photocatalytic C−N Cross‐Coupling from Lab Scale to Multikilogram Scale

    Emily B. Corcoran*a, Jonathan P. McMullen*b, François Lévesqueb, Michael K. Wismerc, John R. Naberb

    • aProcess Research & Development, Merck & Co., Inc., Boston, MA 02115 (USA)
    • bProcess Research & Development, Merck & Co., Inc., Rahway, NJ 07065 (USA)
    • cScientific Engineering & Design, Merck & Co., Inc., Kenilworth, NJ 07033 (USA)
    View abstract

    Visible‐Light‐Mediated Cross‐Couplings and C–H Activation via Dual Photoredox/Transition‐Metal Catalysis in Continuous‐Flow Processes

    Soo Dong Kim, Jonghyun Lee, Nam-Jung Kim, Boyoung Park

    • Kyung Hee University, Department of Pharmacy, Kyungheedaero 26, 02447 Seoul, Republic of Korea
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    A Photoredox Coupling Reaction of Benzylboronic Esters and Carbonyl Compounds in Batch and Flow

    Yiding Chen†, Oliver May†, David C. Blakemore‡, and 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
    View abstract

    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
    View abstract

    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
    View abstract

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

    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
    View abstract

    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
    View abstract

    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
    View abstract

    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
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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
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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
    View abstract

    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
    View abstract

    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
    View abstract

    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
    View abstract

    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
    View abstract

    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
    View abstract

    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
    View abstract

    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
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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
    View abstract

    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
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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
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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
    View abstract

    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
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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
    View abstract

    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
    View abstract

    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)
    View abstract

    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
    View abstract

    Suzuki-Miyaura Cross-Coupling of Heteroaryl Halides and Arylboronic Acids in Continuous Flow

    Timothy Noël, Andrew J. Musacchio

    • Department of Chemistry, MIT, USA
    View abstract

    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

    View abstract

    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
    View abstract

    Application Notes regarding Coupling reactions

    Application Note 49 – Suzuki Coupling with SiliaCat DPP-Pd Heterogeneous Catalyst

    App-note-49-scheme

    In this application, a Vapourtec R-Series has been used to achieve rapid reaction times and high conversion of a Suzuki coupling, using a commercially available supported palladium catalyst. With a reaction time of just 1 min 15 seconds, it was possible to achieve yields of over 80%, at greater than 95% purity following a simple chromatographic separation. This application demonstrates how the Vapourtec R-Series can be used as a tool for the synthetic flow chemist, or for a development chemist beginning the scale up process.

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    Application Note 13: Suzuki Coupling with a Heterogeneous Pd Catalyst

    app-note-13-scheme

    This example illustrates use of a heterogeneous catalyst to perform a Suzuki coupling with high conversion and short residence times.

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