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Updated: Jun 19, 2026
11:45
Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles
Published on: August 22, 2018
Access to N2-Substituted (Aza)Indazoles.
Flora Fan1,2, Xiangfeng Niu3, Wanqi Su1
1Discovery Process Chemistry, Small Molecule Process Research & Development, Merck & Co., Inc., South San Francisco, California 94080, United States.
Organic Letters
|June 18, 2026
Summary
Medicinal chemists developed a new one-pot synthesis for N2-substituted (aza)indazoles, crucial in drug discovery. This efficient method uses readily available starting materials and a key oxidative cyclization for broad applicability.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
- Heterocyclic Chemistry
Background:
- N2-substituted (aza)indazoles are prevalent scaffolds in bioactive molecules and drug candidates.
- Accessing diverse N2-functionalized (aza)indazoles often requires complex synthetic routes.
- Medicinal chemistry programs require efficient and scalable methods for synthesizing novel heterocyclic compounds.
Purpose of the Study:
- To develop a practical and efficient one-pot synthetic method for N2-substituted (aza)indazoles.
- To enable rapid access to a wide range of N2-functionalized (aza)indazoles for drug discovery efforts.
- To establish a scalable and chromatography-free synthesis protocol.
Main Methods:
- A one-pot reaction involving amino (aza)benzaldehydes and various amines.
- Oxidative N-N bond cyclization mediated by phenyliodine(III) diacetate (PhI(OAc)2).
- Scale-up of the reaction for multigram synthesis without chromatography.
Main Results:
- Successful synthesis of diverse N2-substituted (aza)indazoles.
- Demonstration of a key oxidative N-N bond cyclization step.
- Achieved multigram, chromatography-free synthesis, indicating scalability.
Conclusions:
- The developed one-pot method provides a practical and rapid route to N2-substituted (aza)indazoles.
- This protocol is valuable for medicinal chemistry efforts, facilitating the synthesis of drug-like molecules.
- The scalability and chromatography-free nature of the synthesis enhance its utility for producing compounds in larger quantities.
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