Photoredox Iridium–Nickel Dual Catalyzed Cross-Electrophile Coupling: From a Batch to a Continuous Stirred-Tank Reactor via an Automated Segmented Flow Reactor

    • Rohit Duvadiea
    • Alexander Pombergerb
    • Yiming Mob
    • Erhan I. Altinogluc
    • Hsiao-Wu Hsieha
    • Kakasaheb Y. Nandiwalea
    • Victor L. Schultzb
    • Klavs F. Jensenb
    • Richard I. Robinsona
    • aGlobal Discovery Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
    • bDepartment of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
    • cChemical and Pharmaceutical Profiling, Novartis Global Drug Development, 700 Main Street South, Cambridge, Massachusetts 02139, United States

    Organic reaction optimization for batch to flow transfer represents a main challenge for process chemists in drug synthesis. Several factors such as reactant concentration, residence/reaction time, or homo-/heterogeneity need to be taken into consideration during the fine-tuning of reaction conditions toward typical scale-up goals, such as high space–time yield. Herein, we present reaction optimization for photoredox iridium–nickel dual catalyzed cross-electrophile coupling with a focus on developing homogeneous starting conditions. During the screening, special attention was put on the replacement of inorganic bases with homogeneous organic bases, and the effect of pKa on the reaction yield was investigated. Screening was conducted via an automated segmented flow reactor at 15 μL scale, and subsequentially, the conditions were transferred to a 5 mL photo-continuous stirred-tank reactor (CSTR) cascade to demonstrate multigram continuous flow synthesis during a 24 h steady operation.

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