Diversity-oriented functionalization of 2-pyridones and uracils

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Catalysis

Background:

• 2-pyridone and uracil heterocycles are crucial in drug development.
• Efficient synthesis of diverse derivatives is essential for medicinal chemistry.
• Existing methods for functionalizing these scaffolds are limited.

Purpose of the Study:

• To develop a novel dual-functionalization strategy for iodinated 2-pyridones and uracils.
• To enable the efficient synthesis of a wide array of valuable heterocyclic compounds.
• To support drug discovery efforts through rapid access to diverse molecular structures.

Main Methods:

• Palladium/norbornene cooperative catalysis for dual-functionalization.
• Utilized two unique norbornene derivatives as mediators.
• Employed readily available alkyl halides/tosylates and aryl bromides as ortho-functionalization reagents.
• Incorporated diverse ipso-terminating reagents (e.g., H/DCO2Na, boronic acids, alkenes, alkynes).

Main Results:

• Successfully synthesized 79 diverse 2-pyridone and uracil derivatives.
• Prepared deuterium/CD3-labeled 2-pyridones, bicyclic systems, and a fenofibrate conjugate.
• Achieved synthesis of an axially chiral 2-pyridone with 97% enantiomeric excess.
• Demonstrated predictable and efficient preparation of target compounds.

Conclusions:

• The developed palladium/norbornene catalyzed method provides a powerful tool for diversity-oriented synthesis.
• This protocol significantly expands the accessible chemical space of 2-pyridone and uracil derivatives.
• The synthesized compounds hold promise for accelerating new drug discovery initiatives.