ChemBead Enabled High-Throughput Cross-Electrophile Coupling Reveals a New Complementary Ligand.

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Catalysis

Background:

• High-throughput experimentation (HTE) is crucial in medicinal chemistry.
• Existing HTE methods primarily focus on C-N and Csp2-Csp2 bond formation.
• HTE methods for Csp2-Csp3 bond formation are limited, presenting a significant challenge.

Purpose of the Study:

• To adapt nickel-catalyzed cross-electrophile coupling for HTE.
• To enable efficient Csp2-Csp3 bond formation using HTE.
• To map the reactivity space for this transformation.

Main Methods:

• Utilized AbbVie ChemBeads technology for HTE adaptation.
• Employed nickel-catalyzed cross-electrophile coupling of aryl bromides with alkyl halides.
• Executed a large-scale array of 3x222 micromolar reactions.

Main Results:

• Achieved a 56% hit rate, competitive with established HTE reactions.
• Demonstrated scalability of the developed HTE approach.
• Identified bipyridine 6-carboxamidine (BpyCam) as a highly effective and general ligand.

Conclusions:

• The adapted HTE method significantly expands capabilities for Csp2-Csp3 bond formation.
• The ligand BpyCam exhibits broad utility and complementary reactivity, suggesting the existence of "cryptic" catalysts.
• Modern HTE methods are essential for discovering novel and effective catalytic systems.