Fully Automated Flow Protocol for C(sp³)-C(sp³) Bond Formation from Tertiary Amides and Alkyl Halides

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Flow Chemistry

Background:

• Tertiary amides are abundant and versatile chemical feedstocks.
• Efficient C(sp3)-C(sp3) bond formation is crucial for synthesizing complex organic molecules.
• Developing scalable and selective synthetic methods is a key challenge in drug discovery.

Purpose of the Study:

• To develop a novel protocol for C(sp3)-C(sp3) bond formation.
• To utilize readily available tertiary amides as starting materials.
• To establish an automated flow chemistry method for efficient synthesis.

Main Methods:

• Reductive coupling of tertiary amides with in situ generated organozinc reagents.
• Multistep, fully automated flow protocol.
• Gram-scale synthesis starting from bench-stable reagents.

Main Results:

• Successful C(sp3)-C(sp3) bond formation achieved.
• Demonstrated utility in both library synthesis and target molecule synthesis.
• Excellent chemoselectivity and functional group tolerance observed.

Conclusions:

• The developed protocol offers a powerful new tool for organic synthesis.
• The method is suitable for late-stage diversification of drug-like molecules.
• Automated flow chemistry enables scalable and efficient synthesis of valuable compounds.