Combining High-Throughput Experimentation and Automated Flow for Bayesian Optimization of a Metallaphotoredox...

Area of Science:

• Organic Chemistry
• Catalysis
• Chemical Synthesis

Background:

• Metallaphotoredox catalysis enables challenging C-C bond formations.
• Optimization of these reactions often requires extensive screening.
• Developing efficient and sustainable synthetic methods is crucial.

Purpose of the Study:

• To develop an optimized two-stage workflow for metallaphotoredox C(sp2)-C(sp3) coupling.
• To apply high-throughput experimentation (HTE) and Bayesian optimization (BO) for reaction variable selection.
• To extend the coupling reaction to a wider range of substrates, including aryl triflates.

Main Methods:

• A two-stage optimization strategy combining HTE with BO for discrete variables.
• Flow chemistry for fine-tuning continuous reaction parameters.
• Screening of photocatalyst, nickel precursor, ligand, solvent, and amine.

Main Results:

• Identified optimal conditions for C(sp2)-C(sp3) coupling across four aryl (pseudo)halides and alkyl boronic acid pinacol esters.
• Achieved autonomous identification of reactivity trends without prior knowledge.
• Developed DMF- and precious-metal-free protocols, extending the reaction to aryl triflates.

Conclusions:

• The sequential HTE-BO and flow chemistry approach efficiently optimizes metallaphotoredox coupling.
• This strategy enables the development of sustainable and broadly applicable synthetic protocols.
• The study successfully expanded the scope of C(sp2)-C(sp3) coupling to include aryl triflates.