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Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles
Published on: August 22, 2018
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Tandem Amination/Oxetane Ring Opening toward Benzomorpholines
Lindsey G DeRatt1, Chao-Yuan Wang1, Scott D Kuduk1
1Janssen Research and Development, 1400 McKean Road, Spring House, Pennsylvania 19477, United States.
The Journal of Organic Chemistry
|November 22, 2021
Summary
A new tandem method provides efficient access to benzomorpholine scaffolds through C-N coupling and oxetane ring opening. This operationally simple synthesis yields valuable heterocycles in moderate to high yields.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
Background:
- The benzomorpholine scaffold is a key structural motif in various biologically active compounds.
- Efficient synthetic routes to functionalized benzomorpholines are crucial for drug discovery and development.
Purpose of the Study:
- To develop a rapid and operationally simple tandem approach for synthesizing the benzomorpholine scaffold.
- To explore the scope and limitations of the developed method regarding substrate functionalization.
Main Methods:
- A tandem reaction sequence involving C-N coupling (Ullmann or Buchwald-Hartwig conditions) followed by in situ oxetane ring opening.
- Utilizing a range of aryl substrates with diverse functional groups.
Main Results:
- Successful synthesis of benzomorpholine derivatives in moderate to high yields.
- Demonstrated tolerance of various functional groups on the aryl ring.
- The cyclization product features a pendant hydroxymethyl group, enabling further chemical modifications.
Conclusions:
- The reported tandem approach offers a streamlined and efficient route to valuable benzomorpholine heterocycles.
- The method's tolerance for diverse functionalities and the presence of a reactive handle on the product enhance its utility in medicinal chemistry and synthetic endeavors.
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