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.

Addition of Organometallic Reagents to Chiral N‐Methoxylactams: Enantioselective Syntheses of Pyrrolidines and Piperidines

“…reported bottom‐up studies that recently also included achiral and a few racemic monocyclic N‐ alkoxy‐lactams 6. These authors have very recently studied route B → trans ‐ D , which we have not pursued 6a. The steric course of the addition reactions depicted in Scheme is in accordance with general rules concerning additions to iminium ions,6a, 7 that is, preferred axial attack of the nucleophile at the iminum ion in the half‐chair conformation.…”

Chemoselective Reductive Nucleophilic Addition to Tertiary Amides, Secondary Amides, and N‐Methoxyamides

“…Indirect methods require a preactivation step, which is a transformation of the amide functionality into a more reactive species, for example, an acylamide (DeNinno,3a Suh)3c or thioamide (Murai) 3d. e Direct methods, without the preactivation step, proved possible by using tert ‐formamides (de Meijere,3f Bélanger),3i tert ‐amides (Huang),3g, h, m–o sec ‐amides (Huang),3k and N‐alkoxyamides (Kibayashi,4f Sato and Chida,4a, b Vincent and Kouklovsky,4c, d Helmchen) 4e. However, the chemoselective version of the reaction has remained a formidable challenge because of the use of reactive organometallic reagents such as Grignard reagents and organolithium reagents prohibits functional‐group compatibility with sensitive functional groups 7.…”

Approach to Fully Substituted Cyclic Nitrones from N‐Hydroxylactam Derivatives: Development and Application to the Total Synthesis of Cylindricine C

“…To develop the method to provide fully substituted nitrones ( 5 ; R 1 ‐R 3 =alkyl, aryl), we envisioned a nucleophilic addition to the N ‐hydroxyamide derivatives 3 using organolithium reagents, instead of hydride reducing agents (Scheme B). Treatment of 3 with an organolithium reagent would form the five‐membered chelated intermediate 4 .…”