Synthesis and further transformations of 8-chloro-3,4-dihydroisoquinoline

• Published in: Tetrahedron Vol. 74; no. 49; pp. 7009 - 7017
• Main Authors: Hargitai, Csilla, Nagy, Tamás, Halász, Judit, Koványi-Lax, Györgyi, Németh, Gábor, Simig, Gyula, Volk, Balázs
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 06.12.2018; Elsevier
• Subjects: Alkylation; Chemistry; Chemistry, Organic; Cyclization; Friedel-Crafts reaction; Isoquinoline; Lithiation; Physical Sciences; Science & Technology; Suzuki reaction; Isoquinoline; Lithiation; Cyclization; Friedel-Crafts reaction; Alkylation; Suzuki reaction; HALIDES; METALATION; FRIEDEL-CRAFTS ISOMERIZATION; EFFICIENT SYNTHESIS; INHIBITORS; DERIVATIVES
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2018.10.016

Two procedures for the synthesis of barely accessible 8-chloro-3,4-dihydroisoquinoline were investigated. The first approach is based on a directed ortho-lithiation of N-pivaloyl meta-chlorophenylethylamine, followed by formylation and subsequent ring closure under acidic conditions. In the second, more advantageous variant, the N-hydroxyethyl ortho-chlorobenzylamine intermediate undergoes a Friedel-Crafts reaction, and the resulting tetrahydro derivative is oxidized with N-bromosuccinimide. The 8-chloro-3,4-dihydroisoquinoline key intermediate is then applied in Suzuki reactions to give various 8-aryl-3,4-dihydroisoquinolines, which are finally treated with alkyl or aryllithiums to give 1-substituted 8-aryl-1,2,3,4-tetrahydroisoquinolines. These novel 1,2,3,4-tetrahydroisoquinoline derivatives can be used as building blocks in the synthesis of potential drug candidates. [Display omitted]