Regioselective Functionalization of Enamides at the α-Carbon via Unsymmetrical 2-Amidoallyl Cations

Abstract

A new method to functionalize enamides via an intermediacy of unsymmetrical 2-amidoallyl cations is reported. Generated under mild Brønsted acid catalysis, these reactive species were found to undergo addition with various nucleophiles at the less substituted α-carbon to produce highly substituted enamides in high yields with complete control of regioselectivity.

Enantioselective Functionalization of Enamides at the β‐Carbon Center with Indoles

“…We envisioned that stereoablative ionization of this starting material with a chiral Brønsted acid should produce unsymmetric 2‐amidoallyl cation 5 a . In the presence of the readily dissociated triflate counteranion, this intermediate has been shown to undergo nucleophilic capture exclusively at the less substituted α′‐carbon atom to furnish α′‐functionalized enamides 6 . Inspired by this work, we proposed that the activation of substrate 4 with a chiral Brønsted acid invokes a much tighter ion‐pair interaction between the emerging 2‐amidoallyl cation and the bulky chiral anion.…”

“…[5] In the presence of the readily dissociated triflate counteranion, this intermediate has been shown to undergo nucleophilic capture exclusively at the less substituted a'-carbon atom to furnish a'-functionalized enamides 6. [6] Inspired by this work, we proposed that the activation of substrate 4 with ac hiral Brønsted acid invokes am uch tighter ion-pair interaction [7] between the emerging 2-amidoallyl cation and the bulky chiral anion. This critical intermolecular force could consequently introduce substantial steric congestion, thus rendering an attack at the a'-carbon atom kinetically unfavorable.I nt he absence of nucleophilic capture,i ti sc onceivable that an alternative reaction process involving 2-amidoallyl cations could competitively occur considering their presumed high reactivity.…”

“…Our proof-of-concept experiments are summarized in Table 1. [10] Using racemic α-hydroxy enamide (±)- 8 , [6] we began by screening a series of BINOL- and VAPOL-derived phosphoric acids 11a–11g . Ionization of this model substrate with these catalysts in the presence of indole and 4 Å molecular sieves in dichloromethane at room temperature indeed led to preferential functionalization at the β-carbon atom to give (+) -10 as the major product (entries 1–7).…”

Asymmetric Transformations of α-Hydroxy Enamides Catalyzed by Chiral Brønsted Acids

“…aminoallyl cations has recently become a viable method for synthesizing highly functionalized enamides. Kartika and co-workers 6 and Schlegel and Schneider 7 have reported the nucleophilic addition of in-situ-generated 2-aminoallyl cations by a variety of nucleophiles in the presence of achiral Brønsted or Lewis acid catalysts. Driven by the high synthetic value of 2-aminoallyl cations, we were particularly interested in developing related asymmetric catalysis, which had not been realized before 2018.…”

“…4d,9 Kartika and co-workers recently reported a novel method for generating nonsymmetrical 2-aminoallyl cations through Brønsted acid-catalyzed dehydration of αhydroxycyclopentenamides; the cations were then trapped by various nucleophiles (C-nucleophiles or heteroatom nucleophiles) in high yields with complete control of regioselectivity at the less-substituted side. 6 In attempts to establish an asymmetric protocol involving the use of 2-aminoallyl cations, we investigate their counteranions as potent sources of chirality for further asymmetric induction in chiral Brønsted acid catalysis. It is noteworthy that chiral anion catalysis or asymmetric counteranion-directed catalysis, which is based on the ionic interaction between the cationic intermediate and the chiral conjugate base of the catalyst, has become a reliable strategy for a wide range of asymmetric transformations.…”