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.

Rapid and Mild Metal-Free Reduction of Epoxides to Primary Alcohols Mediated by HFIP

“…In hexafluoroisopropanol (HFIP), a solvent known for its H-bond donating ability, the strength of catalytic Brønsted acids is drastically increased, rendering electronically deactivated substrates more reactive . We recently reported an efficient, practical, and broadly applicable Friedel–Crafts arylation of epoxides, including highly deactivated styrene oxides, using catalytic triflic acid (TfOH) in HFIP. , The formed alcohols could undergo a second arylation to access diaryl- and triarylalkanes without preactivation, although this is less efficient when two different nucleophiles were employed. Herein, we demonstrate that this simple catalytic system can be applied to the reduction of epoxides, including electronically deactivated substrates, to rapidly afford the corresponding anti-Markovnikov alcohols at room temperature (Scheme C).…”

Metal-free polychloromethyl radical-initiated cyclization of unactivated N-allylindoles towards pyrrolo[1,2-a]indoles

“…8 For example, the palladium-catalyzed double alkylation of indoles with dihaloalkanes, 9 palladium or photoredox catalyzed intramolecular aromatic alkylation of unactivated alkyl halides, 10 and the transition-metal catalyzed cyclization of N -alkylindoles bearing an olefin group have been successfully utilized for the construction of ring-fused indoles. 11 Besides, the intramolecular Friedel–Crafts cyclizations of substituted methyl 2-(1 H -indole-1-carbonyl)acrylates, 12 Ti( iii ) or HFIP-mediated epoxide opening reactions, 13 transannular ring closure reactions 14 and carbene catalyzed domino ring-opening/redox amidation/Knoevenagel condensation reactions 15 were also efficient approaches towards variously substituted pyrrolo[1,2- a ]indole derivatives. With the development of radical difunctionalization of alkenes and alkynes, 16 the radical cyclization of N -propargylated indoles was successfully utilized in the synthesis of functionalized pyrrolo[1,2- a ]indoles.…”