Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 19, Issue 2, Pages 677-683Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201202639
Keywords
allylation; amides; cyanation; nucleophilic addition; synthetic methods
Categories
Funding
- MEXT [24750045]
- Otsuka Pharmaceutical Co., Japan
- JSPS [24.1843]
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While the synthesis of amide bonds is now one of the most reliable organic reactions, functionalization of amide carbonyl groups has been a long-standing issue due to their high stability. As an ongoing program aimed at practical transformation of amides, we developed a direct nucleophilic addition to N-alkoxyamides to access multisubstituted amines. The reaction enabled installation of two different functional groups to amide carbonyl groups in one pot. The N-alkoxy group played important roles in this reaction. First, it removed the requirement for an extra preactivation step prior to nucleophilic addition to activate inert amide carbonyl groups. Second, the N-alkoxy group formed a five-membered chelated complex after the first nucleophilic addition, resulting in suppression of an extra addition of the first nucleophile. While diisobutylaluminum hydride (DIBAL-H) and organolithium reagents were suitable as the first nucleophile, allylation, cyanation, and vinylation were possible in the second addition including inter-and intramolecular reactions. The yields were generally high, even in the synthesis of sterically hindered alpha-trisubstituted amines. The reaction exhibited wide substrate scope, including acyclic amides, five-and six-membered lactams, and macrolactams.
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