Dearomative Insertion of Fluoroalkyl Carbenes into Azoles Leading to Fluoroalkyl Heterocycles with a Quaternary Center

The skeletal ring expansion of heteroarenes through carbene insertion is gaining popularity in synthetic chemistry. Efficient strategies for heterocyclic ring expansion to access heterocycles containing a fluoroalkyl quaternary carbon center through fluoroalkyl carbene insertion are highly desirable...

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Published in:Angewandte Chemie International Edition 2024-01, Vol.63 (1), p.e202313807-n/a
Main Authors: Li, Linxuan, Ning, Yongquan, Chen, Hongzhu, Ning, Yongyue, Sivaguru, Paramasivam, Liao, Peiqiu, Zhu, Qingwen, Ji, Yong, Ruiter, Graham, Bi, Xihe
Format: Article
Language:English
Subjects:
Azoles
Biocompatibility
Carbenes
Carbon
Dearomatization
Fluoroalkyl Carbenes
Heterocyclic compounds
Insertion
Late-Stage Modifications
Skeletal Editing
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Summary:The skeletal ring expansion of heteroarenes through carbene insertion is gaining popularity in synthetic chemistry. Efficient strategies for heterocyclic ring expansion to access heterocycles containing a fluoroalkyl quaternary carbon center through fluoroalkyl carbene insertion are highly desirable because of their broad applications in medicinal chemistry. Herein, we report a general strategy for the dearomative one‐carbon insertion of azoles using fluoroalkyl N‐triftosylhydrazones as fluoroalkyl carbene precursors, resulting in ring‐expanded heterocycles in excellent yields with good functional‐group compatibility. The broad generality of this methodology in the late‐stage diversification of pharmaceutically interesting bioactive molecules and versatile transformations of the products has been demonstrated. A general skeletal ring expansion strategy was developed for the direct conversion of azoles into various heterocyclic frameworks containing fluoroalkyl‐substituted quaternary centers through dearomative one‐carbon insertion using fluoroalkyl N‐triftosylhydrazones. The method is scalable, tolerates diverse functional groups, and is amenable to the synthesis of medicinally relevant molecules.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202313807