Hexafluoroisopropanol-Mediated Intramolecular Ring-Opening Cyclization of Indolyl- N-Tethered Epoxides: Tether-Length-Controlled Synthesis of 1,7- and 1,2-Fused Indoles

Abstract

Despite having the capability to construct benzo-fused heterocycles in complete atom economy and high chemo-, regio-, enantio-, and diastereoselectivities, intramolecular Friedel-Crafts epoxide arene cyclization (IFCEAC) remains underutilized in organic synthesis. The wide adaptation of this powerful Csp²-Csp³ bond-forming reaction, therefore, requires a broad understanding of the substrate scope to better impact heterocycle synthesis. Along this line, we investigated the applicability of IFCEAC for the synthesis of 1,7- and 1,2-fused indoles. In this article, we report the results of our systematic investigation into the scope and limitations of the first examples of the hexafluoro-2-propanol (HFIP)-mediated IFCEAC of readily accessible indolyl-N-tethered epoxides. We observed that the nature and position of the indole and epoxide substituents and the tether length separating these two reacting moieties have strong effects on the cyclization. This mild and transition-metal-free protocol delivered pyrrolo[3,2,1-ij]quinolin-5-ols in moderate to good yields from substrates bearing both a methylene linker that connects the indole and epoxide moieties and an electron-rich indole carbocyclic ring. Notably, the reactions required the presence of a π-activating aryl substituent on the reacting epoxide carbon atom. Interestingly, replacing the methylene tether with an ethylene unit resulted in regioswitching, which delivered the corresponding tetrahydropyrido[1,2-a]indol-8-ols in good to high yields. We could also successfully extend this methodology to pyrrolyl-N-tethered epoxides for a very high-yielding synthesis of tetrahydroindolizin-7-ols.