The Direct and Enantioselective, One-Pot, Three-Component, Cross-Mannich Reaction of Aldehydes
Yujiro Hayashi*, Wataru Tsuboi, Itaru Ashimine, Tatsuya Urushima, Mitsuru Shoji, Ken Sakai
*Department of Industrial Chemistry, Faculty of Engineering, Tokyo
University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan, Email:
hayashi
ci.kagu.tus.ac.jp
Y. Hayashi, W. Tsuboi, I. Ashimine, T. Urushima, M. Shoji, K. Sakai, Angew. Chem. Int. Ed., 2003, 42, 3677-3680.
DOI: 10.1002/anie.200351813
Abstract
The one-pot, direct cross-Mannich reaction between two different aldehydes has been realized for the first time with high syn-diastereoselectivity and enantioselectivity by use of L-proline as organocatalyst. Side reactions, such as aldol condensation, can be suppressed at low reaction temperatures.
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Details
The document discusses the development of a direct and enantioselective, one-pot, three-component cross-Mannich reaction of aldehydes, led by Yujiro Hayashi and his team. This reaction is significant for constructing chiral nitrogen-containing molecules. Unlike previous methods that used preformed enolates, this approach employs l-proline as an organocatalyst to facilitate the reaction between an aldehyde, 4-methoxyaniline, and a ketone. Initial attempts using propanal and benzaldehyde yielded poor results, but optimizing the reaction temperature to -20°C significantly improved yields and enantioselectivity. The study found that the reaction proceeds more efficiently at lower temperatures, with NMP and DMF as effective solvents. Various aldehydes, including benzaldehyde, p-nitrobenzaldehyde, and p-chlorobenzaldehyde, were tested, showing good yields and high enantioselectivities. The method also works with different donor aldehydes like n-butanal. The success of this reaction lies in its ability to suppress side reactions at low temperatures, making it a valuable tool for synthesizing nitrogen-containing chiral molecules. The study highlights the unique ability of l-proline to activate aldimines preferentially over aldehydes, offering a complementary approach to existing organometal-mediated Mannich reactions.
Key Words
aldehydes, asymmetric synthesis, enantioselectivity, organocatalysis, Mannich Reaction, Multicomponent Reactions
ID: J06-Y2003-630
