Hydrative Aminoxylation of Ynamides: One Reaction, Two Mechanisms

Abstract

Organic synthesis boasts a wide array of reactions involving either radical species or ionic intermediates. The combination of radical and polar species, however, has not been explored to a comparable extent. Herein we present the hydrative aminoxylation of ynamides, a reaction which can proceed by either a polar‐radical crossover mechanism or through a rare cationic activation. Common to both processes is the versatility of the persistent radical TEMPO and its oxidised oxoammonium derivative TEMPO+. The unique mechanisms of these processes are elucidated experimentally and by in‐depth DFT‐calculations.

Chemoselective γ‐Oxidation of β,γ‐Unsaturated Amides with TEMPO

“…A general method for direct, chemoselective γ‐oxidation of unsaturated amides has, however, not emerged yet. Our group has previously studied the interception of keteniminium ions in oxidative contexts beyond the use of N ‐oxides, namely involving the persistent radical TEMPO [22, 23] . Herein, we present an approach to the chemoselective γ‐oxidation of unsaturated amides—to the best of our knowledge, a rare instance of electrophilic amide activation as applied to unsaturated substrates—as well as the intriguing reactivity that is unlocked when this reactivity manifold is leveraged by single‐electron processes.…”

“…Mechanistically, we assume that attack of TEMPO radical on the keteniminium intermediate I [ 22 , 23 ] generates a radical species II which rapidly recombines with a second equivalent of TEMPO at the distal γ‐position to form intermediate III , suggesting a radical–radical cross‐coupling controlled by the persistent radical effect. [27] Fragmentation thereof results in product IV and a ring‐contracted iminium ion V .…”

Chemoselektive γ‐Oxidation von β,γ‐ungesättigten Amiden mit TEMPO

“…Eine generelle Methode für direkte, chemoselektive γ‐Oxidation von ungesättigten Amiden ist bisher noch nicht erforscht. Unsere Arbeitsgruppe hat bereits das Abfangen eines Keteniminiumions im oxidativen Kontext über N ‐Oxide hinaus untersucht, indem das stabile Radikal TEMPO verwendet wurde [22, 23] . Wir präsentieren hier einen Ansatz zur chemoselektiven γ‐Oxidation von ungesättigten Amiden.…”

Catalytic Enantioselective Ynamide Additions to Isatins: Concise Access to Oxindole Alkaloids

“…[8] Thef ully saturated oxazolidine moieties in this ligand type combines au nique ring topology with distinct steric and electronic properties that are remarkably different from bisoxazoline analogues and very useful for asymmetric catalysis. [11] Several examples of enamide-like additions of ynamides to Lewis acid activated carbonyl electrophiles under base-free conditions have been described. Additional screening of various copper and zinc catalysts did not further improve results (entries 9-12 and Supporting Information).…”

“…[10] These observations are in agreement with the enamide-like nucleophilicity of ynamides mentioned above, that is,abase-free C À Cb ond formation occurs via ak eteniminium intermediate followed by tautomerization toward the 3-(aminoethynyl)-3-hydroxyindolin-2-one scaffold. [11] Several examples of enamide-like additions of ynamides to Lewis acid activated carbonyl electrophiles under base-free conditions have been described. [12] Aplausible reaction mechanism that is in agreement with our observations and these reports is shown in Scheme 1.…”