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

• Published in: Angewandte Chemie International Edition Vol. 57; no. 34; pp. 10980 - 10984
• Main Authors: Qian, Guangyin, Bai, Miao, Gao, Shijun, Chen, Han, Zhou, Siwei, Cheng, Hong‐Gang, Yan, Wei, Zhou, Qianghui
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 20.08.2018; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Alkylation; Aromatic compounds; Atom economy; aziridines; Catalysis; Catellani reaction; Chemistry; Chemistry, Multidisciplinary; cooperative catalysis; heterocycles; Palladium; Physical Sciences; Reagents; Regioselectivity; Science & Technology; Stereoselectivity; Substitutes; Substrates; Synthesis; aziridines; ASYMMETRIC-SYNTHESIS; ENANTIOSELECTIVE SYNTHESIS; Catellani reaction; cooperative catalysis; ARYLATION; SEQUENTIAL ARYL-ARYL; N-H; STEREOSPECIFIC SYNTHESIS; FUNCTIONALIZATION; heterocycles; PALLADIUM-CATALYZED SYNTHESIS; CHEMISTRY; palladium; AZA-MICHAEL
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.201806780

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. A modular synthesis of tetrahydroisoquinolines was developed. Aziridines act as the alkylating reagents to enable a Catellani/Heck/aza‐Michael addition cascade by palladium/norbornene (NBE) cooperative catalysis. This mild, chemoselective, and scalable protocol is compatible with a wide range of readily available aryl iodides, aziridines, and olefins. Excellent regio‐ and diastereoselectivities are observed for 1,3‐cis‐substituted and 1,4‐cis‐substituted tetrahydroisoquinolines.