title: Direct nucleophilic addition to N-alkoxyamides.
abstract: 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 α-trisubstituted amines. The reaction exhibited wide substrate scope, including acyclic amides, five- and six-membered lactams, and macrolactams.
authors.affiliation: Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1, Hiyoshi, Yokohama 223-8522, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Yanagita
authors.forename: Hugh
authors.initials: H
authors.lastname: Nakamura
authors.forename: Kenji
authors.initials: K
authors.lastname: Shirokane
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kurosaki
authors.forename: Takaaki
authors.initials: T
authors.lastname: Sato
authors.forename: Noritaka
authors.initials: N
authors.lastname: Chida
mesh_terms: D000577:Amides / Q000737:chemistry*; D007202:Indicators and Reagents / Q000737:chemistry; D007659:Ketones / Q000737:chemistry*; D009584:Nitrogen / Q000737:chemistry*; D009942:Organometallic Compounds / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D000577:Amides; D007202:Indicators and Reagents; D007659:Ketones; D009942:Organometallic Compounds; D009584:Nitrogen