Continuous-Flow Synthesis of Functionalized Phenols by Aerobic Oxidation of Grignard Reagents

Authors

  • Dr. Zhi He,

    1. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 (USA)
    Search for more papers by this author
  • Prof. Dr. Timothy F. Jamison

    Corresponding author
    1. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 (USA)
    • Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 (USA)===

    Search for more papers by this author

  • We are grateful to the Novartis-MIT Center for Continuous Manufacturing for financial support. We thank several colleagues at MIT (Dr. Yuan Zhang, Dr. Ping Zhang, and Dr. Jie Wu) and at Novartis (Dr. Berthold Schenkel, Dr. Gerhard Penn, and Dr. Benjamin Martin) for insightful discussions.

Abstract

Phenols are important compounds in chemical industry. An economical and green approach to phenol preparation by the direct oxidation of aryl Grignard reagents using compressed air in continuous gas-liquid segmented flow systems is described. The process tolerates a broad range of functional groups, including oxidation-sensitive functionalities such as alkenes, amines, and thioethers. By integrating a benzyne-mediated in-line generation of arylmagnesium intermediates with the aerobic oxidation, a facile three-step, one-flow process, capable of preparing 2-functionalized phenols in a modular fashion, is established.

Ancillary