Modular One‐Step Three‐Component Synthesis of Tetrahydroisoquinolines Using a Catellani Strategy

Abstract

Reported is a modular one-step three-component synthesis of tetrahydroisoquinolines using a Catellani strategy. This process exploits aziridines as the alkylating reagents, through palladium/norbornene cooperative catalysis, to enable a Catellani/Heck/aza-Michael addition cascade. This mild, chemoselective, and scalable protocol has broad substrate scope (43 examples, up to 90 % yield). The most striking feature of this protocol is the excellent regioselectivity and diastereoselectivity observed for 2-alkyl- and 2-aryl-substituted aziridines to access 1,3-cis-substituted and 1,4-cis-substituted tetrahydroisoquinolines, respectively. Moreover, this is a versatile process with high step and atom economy.

para‐Selective Arylation of Arenes: A Direct Route to Biaryls by Norbornene Relay Palladation

“…Hence, it was important to provide an ortho ‐substitution to ensure the necessary steric pulse. The proposition was also established by the study of Catellani and Dong [15b–d,k] . It was found that the β‐carbon elimination was facilitated by the presence of ortho ‐disubstitution.…”

para‐Selective Arylation of Arenes: A Direct Route to Biaryls by Norbornene Relay Palladation

“…To diversify the scope of sulfonate scaffolds we tested several aryl iodides bearing ester ( 3 a and 3 b ) or nitro ( 3 c ) groups to provide the desired para ‐arylated compounds in good to excellent yields and selectivity. As mentioned earlier, 2,6‐disubstitution was unavoidable [12, 15b–d, k] to harness the desired palladium relay reactivity to achieve para ‐selective arylation. Therefore, we diversified the scope of arenes with respect to various 2,6‐disubstituted templates.…”

Transition Metal Promoted Cascade Heterocycle Synthesis through C−H Functionalization

“…Zhou and co‐workers, in 2018, reported a powerful method for the synthesis of tetraidroisoquinolines 142 or 143 starting from simple aryl‐iodides 131 , aziridines 140 and electron‐poor olefins 141 . The protocol tolerates various substituents on both the aryl‐iodide, the aziridine as well as the olefin allowing to access to the tetraidroisoquinoline scaffold in good yields (Scheme ).…”