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Nickel-Catalyzed Cross-Electrophile Coupling to Access Polysubstituted Cyclobutenes
Zining Liu1, Yandong Wang1,2, Jiahui Yu1
1Key Laboratory of Functional Molecular Engineering of Guangdong Province, Guangzhou, 510640, P.R. China.
Angewandte Chemie (International Ed. in English)
|May 13, 2025
Summary
This study introduces an efficient nickel-catalyzed coupling method for synthesizing polysubstituted cyclobutenes. This novel reductive cyclization offers a streamlined route to complex molecules, including pharmaceutical compounds.
Area of Science:
- Organic Chemistry
- Catalysis
- Synthetic Methodology
Background:
- Cyclobutene synthesis is challenging due to ring strain and regioselectivity issues.
- Existing methods often lack efficiency and broad applicability.
Purpose of the Study:
- To develop a novel, efficient method for synthesizing polysubstituted cyclobutenes.
- To establish a reliable route for accessing diverse cyclobutene-containing compounds.
Main Methods:
- Nickel-catalyzed cross-electrophile coupling (XEC) of homopropargyl halides with aryl/vinyl electrophiles.
- Utilizing a reductive 4-endo-dig cyclization strategy.
- Mechanistic investigations including experimental data and computational studies.
Main Results:
- Achieved direct access to polysubstituted cyclobutenes with high chemo- and regioselectivity.
- Demonstrated the first reductive 4-endo-dig cyclization for cyclobutene synthesis.
- Optimized the synthesis of a combretastatin A-4 analog from 14% to 51% yield in fewer steps.
- Identified an alkenyl nickel(I) intermediate mechanism with stereoinversion.
Conclusions:
- The developed nickel-catalyzed XEC is a powerful tool for constructing polysubstituted cyclobutenes.
- This method enables efficient synthesis of complex cyclobutene derivatives, including macrocycles.
- The optimized route significantly improves the synthesis of biologically active compounds.
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