Diastereoselective Synthesis of Perfluoroalkylmethyl‐Substituted 1,2,3,4‐Tetrahydroquinolines Derivatives through 1‐Iodo‐1,3‐bis(acetoxy) Synthons

Abstract

Novel 2‐perfluoroalkylmethyl,4‐arylamino substituted tetrahydroquinolines (THQ) were expeditiously synthesized from perfluoroalkyl iodides RF−I and monosubstituted anilines. First, radical bis‐addition of vinyl acetate on RF−I afforded gem‐iodoacetoxy derivatives (newly characterized by NMR and MS) being actually masked/activated aldol synthons. Their reaction in 1 : 4 ratio with arylamines afforded title THQ under mild conditions in good yields (60–95 %) and diastereoselectivities (65 : 35–95 : 5 cis/trans isomer ratio); m‐substituted anilines regiospecifically lead to 7‐substituted THQ. Mechanistic investigation suggested the THQ formation to proceed through Michael then imine addition of two aniline units on an RF‐substituted crotonaldehyde intermediate, then through the cyclization of the resulting bis(arylamino/imino) intermediate through electrophilic aromatic substitution. Various RF (C6, C2, C4) and arylamine substitutions (p‐,o‐,m‐ alkyl, alkoxyl, halogen…) were thus exemplified.