Divergent Pyridine-to-Pyrazole Conversion via Carbon-Retentive Skeletal Editing
Hyeonsoo Han1,2, Xiangzhang Tao1,2, Heeho Noh1,2
1Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon34141, Korea.
Journal of the American Chemical Society
|July 23, 2026
Summary
This study introduces a novel method for regioselective pyrazole synthesis, overcoming key challenges in medicinal chemistry. The approach uses carbon-retentive skeletal editing for predictable access to diverse pyrazole structures from pyridines.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Chemical Biology
Background:
- Regioselective pyrazole synthesis is challenging due to difficulties in controlling N-differentiation.
- Existing methods often struggle with molecular complexity and regiochemical control.
Purpose of the Study:
- To develop a novel platform for regioselective pyrazole synthesis.
- To enable predictable access to diverse pyrazole architectures from common pyridines.
- To circumvent regioselectivity limitations in medicinal chemistry.
Main Methods:
- Carbon-retentive skeletal editing of pyridines.
- Mechanistically divergent pathways: photochemical radical deconstruction-rearrangement and thermal polar reorganization.
- One-pot reactions under mild conditions.
Main Results:
- Structurally distinct pyrazoles were synthesized from a single pyridine precursor.
- Photochemical pathway yielded aldehyde- or amine-substituted pyrazoles.
- Thermal pathway with hydrazines provided orthogonal substitution patterns.
- The method accommodates complex pharmaceuticals.
Conclusions:
- A divergent synthetic platform provides predictable access to complementary pyrazole architectures.
- This approach expands accessible chemical space for drug discovery by overcoming regioselectivity challenges.
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