Accessing Diverse Azole Carboxylic Acid Building Blocks via Mild C-H Carboxylation: Parallel, One-Pot Amide Couplings...

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Heterocyclic Chemistry

Background:

• Direct functionalization of C-H bonds in heterocycles is crucial for synthesizing complex molecules.
• Existing methods for azole functionalization often require harsh conditions or metal catalysts.
• Expanding the accessible chemical space of azole derivatives is important for drug discovery and materials science.

Purpose of the Study:

• To develop a mild, metal-free C-H carboxylation method for azoles.
• To enable direct access to azole-2-carboxylic acids and their amide derivatives in a one-pot procedure.
• To demonstrate the broad utility and transferability of the developed protocol for library synthesis.

Main Methods:

• Metal-free C-H carboxylation using silyl triflate reagents.
• One-pot amide coupling following carboxylation.
• Machine-learning-guided substrate scope analysis.
• Density functional theory (DFT) calculations for mechanistic insights.

Main Results:

• Successful synthesis of diverse azole-2-carboxylic acids and azole-2-amides.
• Demonstrated functional group tolerance and mild reaction conditions.
• Established transferrable applications including low-pressure CO2 utilization, 13CO2 labeling, and direct C-H amidation with isocyanates.
• Achieved a 90% library success rate in a parallel synthesis workflow.

Conclusions:

• The developed protocol offers a significant expansion of accessible azole-2-amides.
• Silyl triflates are key mediators for C-H deprotonation and stabilization of intermediates.
• The methodology enables efficient library synthesis and provides access to valuable building blocks.