Expedited Aminoglutarimide C-N Cross-Coupling Enabled by High-Throughput Experimentation

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Catalysis

Background:

• Cereblon binding motifs are crucial in drug discovery and chemical biology.
• Existing synthetic routes for these motifs can be lengthy and complex.
• Development of efficient C-N cross-coupling reactions is essential for accessing diverse chemical structures.

Purpose of the Study:

• To disclose a simple and efficient protocol for the Buchwald-Hartwig cross-coupling of (hetero)aryl halides with unprotected aminoglutarimide.
• To generate diverse cereblon binding motifs.
• To establish a method with strategic superiority over existing synthetic approaches.

Main Methods:

• High-throughput screening of solvents, bases, temperatures, and ligands to optimize the Buchwald-Hartwig cross-coupling reaction.
• Utilized unprotected aminoglutarimide and various (hetero)aryl halides as substrates.
• Investigated reaction scope and conditions.

Main Results:

• A simple and effective protocol for C-N cross-coupling was successfully developed.
• The reaction proceeds under mild conditions and shows generality across a range of heteroaryl and aryl halides.
• The method significantly reduces the step count compared to previously reported syntheses.

Conclusions:

• The developed Buchwald-Hartwig cross-coupling protocol provides a facile route to diverse cereblon binding motifs.
• This method offers a strategic advantage due to its simplicity, efficiency, and reduced step count.
• The protocol is valuable for the synthesis of potential therapeutic agents and chemical probes.