HFIP-Empowered One-Pot Synthesis of C4-Aryl-Substituted Tetrahydroquinolines with Propargylic Chlorides and Anilines

Transition-metal-free, practical one-pot synthesis of C4-aryl-substituted tetrahydroquinolines from simple anilines and readily accessible propargylic chlorides has been developed. Activation of the C-Cl bond by 1,1,1,3,3,3-hexafluoroisopropanol turned out to be the key interaction, which allowed C-N bond formation under an acidic medium. Propargylated aniline is formed as an intermediate via propargylation, and subsequential cyclization and reduction gave 4arylated tetrahydroquinolines. To demonstrate the synthetic utility, total syntheses of aflaquinolone F and I have been accomplished.

Automated summary

In this study, a transition-metal-free, practical one-pot synthesis of C4-aryl-substituted tetrahydroquinolines from simple anilines and readily accessible propargylic chlorides was developed. The key interaction was the activation of the C-Cl bond by 1,1,1,3,3,3-hexafluoroisopropanol, which allowed for C-N bond formation under an acidic medium. Demonstrating the synthetic utility, the total syntheses of aflaquinolone F and I were accomplished.