Transition-Metal-Free Cross-Coupling of Acetals and Grignard Reagents To Form Diarylmethyl Alkyl Ethers and Triarylmethanes
Yang Qin, Sheng Liu, Shi-Liang Shi*
*Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. of China, Email:
shiliangshi
sioc.ac.cn
Y. Qin, S. Liu, S.-L. Shi, Synthesis, 2024, 56, 527-538.
DOI: 10.1055/a-2088-5000
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Abstract
A transition-metal-free cross-coupling reaction of acetals and Grignard reagents provides ethers in high yields. A series of readily accessible acetals bearing aryl, alkenyl, and alkyl substituents efficiently coupled with commercially available aryl, alkyl, and allylic magnesium bromides. A sequential difunctionalization of acetals led to the rapid synthesis of triarylmethanes and diarylalkanes.
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Details
The document reports a transition-metal-free cross-coupling reaction of acetals and Grignard reagents, enabling the synthesis of diarylmethyl alkyl ethers, triarylmethanes, and 1,1-diarylalkanes. These compounds are significant in pharmaceuticals and bioactive molecules. The method involves coupling various acetals with commercially available Grignard reagents, yielding products in high efficiency. The reaction is optimized using octane as the solvent at 100°C, achieving up to 99% yield. The scope includes benzylic, alkenyl, and alkyl acetals, as well as cyclic acetals, ketals, and orthoesters. The reaction mechanism likely involves a Lewis acid-mediated nucleophilic addition via a carbocation intermediate. The study also explores the generality of Grignard reagents, including aryl, alkyl, and allylic types, and demonstrates the method's scalability. The findings provide a practical and modular approach for synthesizing complex molecules, with potential applications in medicinal chemistry and organic synthesis. The research is supported by the National Key Research and Development Program of China and the National Natural Science Foundation of China. The document includes detailed experimental procedures, characterization data, and references to previous related works.
Key Words
ID: J66-Y2024
