Immobilized Carbodiimide Assisted Flow Combinatorial Protocol to Facilitate Amide Coupling and Lactamization

Area of Science:

• Organic Chemistry
• Flow Chemistry
• Polymer-Supported Synthesis

Background:

• Traditional amide coupling and lactamization methods often involve multiple steps, harsh conditions, and potential for side reactions.
• Carbodiimide reagents are widely used but can suffer from issues like racemization and difficult purification.
• Developing more efficient, safer, and scalable synthetic protocols is crucial for organic synthesis and drug discovery.

Purpose of the Study:

• To develop a convenient and novel carbodiimide polymer-assisted flow approach for amide coupling and lactamization.
• To optimize reaction conditions including temperature, solvents, carbodiimide resins, and additives.
• To evaluate the efficiency, yield, and safety (racemization) of the developed flow protocol.

Main Methods:

• Extensive screening of over 130 permutations of reaction parameters (temperature, solvents, carbodiimide resins, equivalents, additives).
• Development of a continuous flow protocol involving injection of a single solution of carboxylic acid and amine/peptide into a dichloromethane stream.
• Utilized a polymer-supported carbodiimide reagent in a flow system, with investigation of diisopropylamine and benzotriazole additives.

Main Results:

• A convenient carbodiimide polymer-assisted flow method for amide coupling and lactamization was successfully developed.
• The protocol achieved high product yields with minimal workup, even in the absence of base and without carboxylate preactivation.
• The flow procedure demonstrated improved safety against racemization compared to conventional untethered carbodiimide reagents.

Conclusions:

• The developed polymer-assisted flow chemistry approach provides an efficient, high-yielding, and safer alternative for amide and lactam synthesis.
• This method simplifies the synthetic process by enabling single-solution injection and minimizing purification steps.
• The protocol's robustness and reduced racemization make it a valuable tool for peptide synthesis and medicinal chemistry.