Tandem Synthesis of 2-Carboxybenzofurans via Sequential Cu-Catalyzed C-O Coupling and Mo(CO)6-Mediated Carbonylation Reactions
Qinliang Mo, Nan Sun*, Liqun Jin, Baoxiang Hu, Zhenlu Shen and Xinquan Hu*
*College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310032, P. R. China,
Email: sunnanzjut.edu.cn, xinquan
zjut.edu.cn
Q. Mo, N. Sun, L. Jin, B. Hu, Z. Shen, X. Hu, J. Org. Chem., 2020, 85, 11490-11500.
DOI: 10.1021/acs.joc.0c01620
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Abstract
A synthesis of 2-carboxybenzofurans from 2-gem-dibromovinylphenols is based on Cu-catalyzed intramolecular C-O coupling followed by Mo(CO)6-mediated intermolecular carbonylation. This protocol provides a broad range of functionalized benzofuran-2-carboxylic acids, esters, and amides in very good yields under Pd- and CO gas-free conditions.
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Details
The article discusses a novel tandem synthesis method for 2-carboxybenzofurans from 2-gem-dibromovinylphenols using a sequence of Cu-catalyzed intramolecular C−O coupling and Mo(CO)6-mediated intermolecular carbonylation reactions. This method allows for the efficient one-step synthesis of benzofuran-2-carboxylic acids, esters, and amides without the need for Pd catalysts or CO gas. The process is significant for its application in medicinal chemistry, particularly in the synthesis of bioactive molecules like Vilazodone, an antidepressant. The study highlights the optimization of reaction conditions, demonstrating that the copper catalyst, ligand, and base are essential for high yields. Various alcohols and amines were tested, showing good to excellent yields for a range of functionalized benzofuran derivatives. The method's practicality was further validated by successful gram-scale syntheses. The proposed reaction mechanism involves the formation of 2-bromobenzofuran intermediates, which then undergo carbonylation facilitated by Mo(CO)6. This new protocol is advantageous due to its safety, ease of operation, and the avoidance of precious metal catalysts, making it attractive for organic and medicinal chemists.
Key Words
benzofurans, multicomponent reactions
ID: J42-Y2020