Synthesis of Tetrahydroisoquinolines via Cascade Reductive Amination of Isochromenylium Tetrafluoroborate with Primary Amines

Abstract

Reactions of isochromenylium tetrafluoroborates with various primary amines have been investigated under reductive amination conditions. The established cascade methodology provides a convenient one-step synthesis of various tetrahydroisoquinoline derivatives under mild conditions.

Isochromenylium/Isoquinolinium-Mediated One-Pot Annulation to Hexahydropyrazinoisoquinolines. Synthesis of Quinocarcinol

“…Therefore, it is of great significance to design a new general protocol for efficient construction of hexahydropyrazinoisoquinolines and overcoming the aforementioned disadvantages (Figure b). Based on our previous study on isochromenylium-mediated transformations, o -alkynyl benzaldehyde 2 with an embedded N -Me group in the alkyne–amine side chain was applied as the annulation precursor. We expect that initially in situ generated isochromenylium could be converted into the corresponding isoquinolinium via an intramolecular dehydrated N → O replacement with the preequipped terminal amine functionality, and subsequent full reduction of the B ring would deliver the ABC-ring system of hexahydropyrazinoisoquinolines in a concise way.…”

“…Considering the roles of Brönsted acid during the isochromenylium formation and substrate properties, we deduced that increasing TFA equivalents might balance the basicity of internal tertiary amine and favor the reaction progress. Delightedly, significant improvement was observed when using increasing quantities of TFA (entries 2 and 3).…”