Copper(I)-Catalyzed Ketenimine Formation/Aza-Claisen Rearrangement Cascade for Stereoselective Synthesis of α-Allylic Amidines

Abstract

A copper-catalyzed three-component reaction of terminal alkynes, TsN 3 , and tertiary allylic amines is developed toward the one-pot synthesis of αallylic amidines. The product was synthesized on gram scale under 1 mol % of catalyst loading. Transformations of products into alkenyl amine and other nitrogen-containing compounds are demonstrated without any loss of stereochemical information.

Recent Advances in Catalytic [3,3]-Sigmatropic Rearrangements

“…Aza-Claisen rearrangement occurs through the Cu-activated alkyne 101, and intramolecular cyclization and protodemetalation ensue the formation of the desired 2,3-disubstituted indoles 100. Cao's group developed the copper(I)-catalyzed stereoselective synthesis of α-allylic amidines 104 via cascade ketenimine formation and aza-Claisen rearrangement (Scheme 20) [49]. The reaction was successfully demonstrated on the gram scale using only 1 mol% catalyst in a one-pot synthesis with three components, namely, the terminal alkyne 102 and TsN3, and tertiary allylic amine 103.…”

“…Cao's group developed the copper(I)-catalyzed stereoselective synthesis of α-allylic amidines 104 via cascade ketenimine formation and aza-Claisen rearrangement (Scheme 20) [49]. The reaction was successfully demonstrated on the gram scale using only 1 mol% catalyst in a one-pot synthesis with three components, namely, the terminal alkyne 102 and TsN 3 , and tertiary allylic amine 103.…”

Asymmetric Aza-Claisen Rearrangement between Enantioenriched α-Chiral Allylamines and Allenones

“…Charge acceleration has been frequently employed as a powerful strategy to decrease the reaction temperature via converting allylamines into the corresponding ammonium salts through protonation, Lewis acid coordination, or quaternization prior to the aza-Claisen rearrangement. Particularly, zwitterionic aza-Claisen rearrangements can proceed under relatively mild conditions after nucleophilic addition of tertiary allylamines to π-electrophiles such as 2-alkynoates, acetylenic sulfones, allenoates, ketenes, , ketenimines, carbodiimides, isocyanates, and isothiocyanates . While stereochemical advantages can be expected from the aza-Claisen rearrangements because of their chair-like six-membered transition states with minimized repulsive interactions, only l -(−)-proline-derived α-chiral allylamines have been reported previously to exhibit effective 1,3-chirality transfer in the ketene-mediated rearrangement/ring-expansion reaction (Scheme a). ,, To our knowledge, 1,3-chirality transfer has not yet been disclosed for the aza-Claisen rearrangement of other types of enantioenriched α-chiral allylamines, which, though, can be readily accessible by resolution of the racemic ones with inexpensive chiral acids .…”

“…Inspired by previous reports on the zwitterionic aza-Claisen rearrangements of π-electrophile-activated tertiary allylamines, − we initiated our investigation on a possible asymmetric aza-Claisen rearrangement between enantioenriched α-chiral allylamines and allenones, wherein retention of enantiopurity was expected via a chair-like six-membered transition state with minimized repulsive interactions (Scheme b). To our delight, simply treating allylamine rac - 1a with allenone 2a in dichloromethane at room temperature afforded β-amino enone rac -3a in 85% NMR yield (Table , entry 1).…”

Radical Chain Isomerization of N-Sulfonyl Ynamides to Ketenimines and Its Application to Furan Dearomatization

“…Consequently, they serve as valuable building blocks for the preparation of nitrogen-containing compounds. Traditionally, ketenimines can be prepared by the Wittig reaction of isocyanates, the aza-Wittig reaction of ketenes, the transition metal-catalyzed cross-coupling of isocyanides, and Cu-catalyzed azide–alkyne cycloaddition . Most of these methods rely on the in situ generation of ketenimines, which undergo further transformation without prior isolation.…”