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HFIP-Promoted One-Pot Synthesis of Indolines and Pyrrolidines
Seung Hoon Lee1, Seung Woo Hong1, Hyung Min Chi1,2
1Department of Chemistry, Pohang University of Science and Technology, Pohang 37673, South Korea.
The Journal of Organic Chemistry
|May 20, 2026
Summary
A new one-pot synthesis method for N-heterocycles using readily available starting materials in hexafluoroisopropanol (HFIP) has been developed. This efficient approach yields valuable indoline and pyrrolidine derivatives, showcasing broad functional group tolerance.
Area of Science:
- Organic Chemistry
- Synthetic Chemistry
Background:
- N-heterocycles are crucial structural motifs in pharmaceuticals and natural products.
- Efficient synthetic routes to substituted indolines and pyrrolidines are highly sought after.
Purpose of the Study:
- To develop a practical and efficient one-pot method for synthesizing N-heterocycles.
- To explore the use of hexafluoroisopropanol (HFIP) as a reaction medium for sequential alkylation and cyclization.
Main Methods:
- Utilizing readily available amines and alkyl halides as starting materials.
- Employing acidic conditions in HFIP to facilitate a one-pot sequential alkylation and cyclization process.
- Characterizing the synthesized indoline and pyrrolidine derivatives using standard analytical techniques.
Main Results:
- A range of indoline and pyrrolidine derivatives were successfully synthesized.
- Moderate to good yields were achieved with notable tolerance for diverse functional groups and nitrogen substitution patterns.
- The method demonstrated scalability through gram-scale reactions and utility in synthesizing complex molecules, including a formal synthesis of cephalotaxine.
Conclusions:
- The developed method provides a practical and versatile route to N-heterocycles.
- HFIP facilitates a novel one-pot sequential alkylation-cyclization strategy under acidic conditions.
- The synthetic approach is valuable for accessing functionalized pyrrolidines and indolines, with potential applications in drug discovery and natural product synthesis.
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