Automated library generation using sequential microwave-assisted chemistry. Application toward the Biginelli...

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Automation and Robotics

Background:

• Microwave-assisted synthesis offers accelerated reaction rates.
• Automated systems are crucial for high-throughput screening and combinatorial chemistry.
• The Biginelli reaction is a key multicomponent reaction for synthesizing dihydropyrimidines (DHPMs).

Purpose of the Study:

• To introduce and demonstrate automated sequential microwave-assisted library synthesis.
• To develop a robotic platform for efficient and flexible synthesis of DHPM libraries.
• To optimize reaction conditions for automated Biginelli cyclocondensation.

Main Methods:

• A single-mode microwave reactor integrated with a liquid handler and robotic gripper was utilized.
• Automated dispensing of reagents and sequential microwave irradiation of individual reaction vials were performed.
• A diverse library of DHPMs was synthesized using various CH-acidic carbonyl compounds, aldehydes, and urea/thioureas.

Main Results:

• A subset of 48 DHPM analogues was synthesized from a potential pool of 3400 derivatives.
• Optimized conditions (10 min microwave heating, 120°C, AcOH/EtOH, Yb(OTf)3 catalyst) yielded an average of 52% isolated DHPMs with >90% purity.
• The system demonstrated flexibility in adjusting reaction parameters for different building block combinations.

Conclusions:

• Automated sequential microwave synthesis provides a flexible and efficient platform for combinatorial library generation.
• The developed robotic system significantly reduces synthesis time, enabling the production of large DHPM libraries within hours.
• This approach facilitates rapid access to diverse chemical scaffolds for drug discovery and materials science.