Regio- and Stereocontrolled-Synthesis of a Heterocycle Fragment Collection Using Palladium Catalyzed C-H Arylation

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Saturated heterocycles are crucial in drug discovery, offering desirable polarity and 3D structures.
• Controlled functionalization of these heterocycles is challenging, limiting access to diverse chemical entities.
• Existing methods often lack control over substitution patterns and require pre-functionalized starting materials.

Purpose of the Study:

• To develop a systematic method for controlling the position and orientation of exit vectors in heterocycles.
• To synthesize a structurally diverse collection of saturated heterocyclic fragments using a novel C-H functionalization strategy.
• To enable access to novel chemical matter for drug discovery programs.

Main Methods:

• Utilized aminoquinoline-directed C-H functionalization for regioselective functionalization of heterocycles.
• Employed directing groups at C(2), C(3), or C(4) positions to achieve site-specific β-arylation.
• Developed a strategy for subsequent removal of directing groups to reveal diverse functional handles such as carboxylic acids, amides, alcohols, and nitriles.

Main Results:

• Successfully synthesized 44 novel saturated heterocyclic fragments with controlled exit vectors.
• Demonstrated the versatility of the method across five- and six-membered N-heterocycles, and rings containing sulfonyl and difluoromethylene units.
• The synthesized fragments exhibit structural novelty and favorable physicochemical properties, enhancing AbbVie's compound collection.

Conclusions:

• The reported aminoquinoline-directed C-H functionalization provides a powerful and systematic approach for synthesizing diverse heterocyclic fragments.
• This method overcomes limitations of previous techniques, enabling precise control over functionalization and access to novel chemical space.
• The resulting fragment library offers significant potential for accelerating drug discovery efforts.