Organometallic Chemistry in Flow

    Organometallic compounds are organic compounds incorporating carbon-metal bonds.  Organometallic compounds have been known and studied for nearly 200 years, and their unique properties have been widely used in synthetic transformations.  Depending on the reduction potential of the metal, the reactivity of organometallic compound can vary greatly. The most reactive compounds require low to moderate temperatures and inert conditions (atmosphere and solvents) for preparation and use and the highly reactive compounds can be pyrophoric.

    Continuous flow chemistry is an excellent tool for undertaking reactions utilising organometallic reagents for many reasons; precise control of reaction temperature, time and mixing, low volume sealed system so easily maintained dry and inert,  efficient to keep continuous reactors cool when compared with batch reactors,  improved safety  through lower inventory of hazardous materials and handling of pyrophoric reagents eliminated.

    Examples of published literature for Organometallic Chemistry in Flow

    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
    View abstract

    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
    View abstract

    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
    View abstract

    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
    View abstract

    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
    View abstract

    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
    View abstract

    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
    View abstract

    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
    View abstract

    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
    View abstract

    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
    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

    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
    View abstract

    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
    View abstract

    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
    View abstract

    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
    View abstract

    Application Notes regarding Organometallic Chemistry in Flow

    Application Note 35 – Reaction of Grignard Reagents using the E-Series

    app_note35

    This application note illustrates the use of the Vapourtec E-Series system to run reactions such as Grignard reactions under continuous flow conditions for extended periods with no pump issues.

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    Application Note 34 – Reaction of Organolithium Reagents using the E-Series

    app_note34

    This application note illustrates the use of the Vapourtec E-Series system to run organometallic reagents such as n-Butyl lithium under continuous flow conditions.

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    Application Note 33 : Chromium Arene Synthesis

    app_note33

    This application note demonstrates the preparation of arene chromium tricarbonyl complexes using continuous-flow processing: (η6C6H5CH3)Cr(CO)3 as an example.

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