Catalytic Generation of Indium Hydride in a Highly Diastereoselective Reductive Aldol Reaction

Ikuya Shibata*, Hirofumi Kato, Tatsuya Ishida, Makoto Yasuda, Akio Baba

*Department of Molecular Chemistry, Science and Technology Center for Atom, Molecules and Ions Control, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan, Email: shibatachem.eng.osaka-u.ac.jp

I. Shibata, H. Kato, T. Ishida, M. Yasuda, A. Baba, Angew. Chem. Int. Ed., 2004, 43, 711-714.

DOI: 10.1002/anie.200352738

Abstract

An Et₃SiH-promoted diastereoselective reductive aldol reaction has been developed using InBr₃ as a catalyst. This three-component reaction afforded only silyl aldolates as products without any side reactions.

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proposed mechanism

Details

The reductive aldol reaction using metal hydrides, enones, and aldehydes is a valuable method for synthesizing β-hydroxyketones. Traditional methods face challenges due to the sensitivity of aldehydes and the need for pre-synthesized metal enolates. This study introduces a superior method using catalytic indium halides (InBr₃) and hydrosilanes (Et₃SiH) instead of nBu₃SnH, eliminating the need for pre-synthesized indium hydrides. The Et₃SiH/InCl₃ system initially showed low yields, but switching to EtCN solvent improved the yield significantly. The method achieves high diastereoselectivity, favoring syn-aldolates, and avoids the reduction of aldehydes, a common issue with other systems. The catalytic cycle involves the slow transmetalation of InBr₃ with Et₃SiH to generate Br₂InH, which then promotes the 1,4-reduction of enones to form indium enolates. These enolates react with aldehydes to form syn-aldolates, which are trapped by Et₃SiH. The method is effective for various aromatic and aliphatic aldehydes and enones, providing high yields and selectivity. This approach offers a more efficient and selective route for reductive aldol reactions, with the added benefit of easy removal of silicon compounds post-reaction.

Key Words

aldol reaction, diastereoselectivity, hydroxyketones, indium, triethylsilane, reductive aldol addition, Multicomponent Reactions

ID: J06-Y2004-090