Direct Amidation of Tertiary N-Benzylamines

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• Protecting groups are essential in complex synthesis but present challenges in efficiency and cleavage.
• Standalone protecting group manipulations are often inefficient and difficult with polyfunctional molecules.
• Developing methods to leverage protecting groups as functional handles is crucial for synthetic efficiency.

Purpose of the Study:

• To develop a method for direct amidation of tertiary N-benzylamines.
• To utilize protecting groups as handles for desired functionalization, bypassing traditional drawbacks.
• To synthesize medicinally important amides, including acrylamides, with high yields and broad functional group tolerance.

Main Methods:

• Direct amidation of tertiary N-benzylamines under mild conditions.
• Utilizing N-benzyl protecting groups as reactive handles for functionalization.
• Demonstrating broad functional group tolerance in amide synthesis.

Main Results:

• Achieved direct amidation of tertiary N-benzylamines with high yields.
• Synthesized medicinally relevant acrylamides and a variety of other amides.
• Showcased broad functional group tolerance, indicating method versatility.

Conclusions:

• The developed method efficiently converts N-benzyl protecting groups into amide functionalities.
• This approach simplifies complex molecule synthesis and endgame strategies for Active Pharmaceutical Ingredients (APIs).
• The utility is demonstrated in the synthesis of sensitive acrylamide APIs, such as the KRAS^G12C inhibitor MK-1084.