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.

The regio- and diastereoselective construction of biologically relevant cyclic carbamates under operationally simple and mild transition metal-free is challenging and has led to a demand for efficient methods for their synthesis. The intramolecular ring-opening cyclization of N-Boc-tethered epoxides leading to the formation of cyclic carbamates is equipped with many favorable synthetic features, including easy accessibility of starting materials in a stereodefined form, high diversification points in the substrates, and favorable entropy factor. However, its use in the construction of 1,3-oxazinan-2-ones remains largely neglected. Specifically, prior to 2020, only few 1,3-oxazinan-2-ones were successfully synthesized using this strategy. Moreover, our very own recent attempt to access these heterocycles using one-carbon-tethered N-Boc/epoxide pairs was met with a little success as the process furnished either only 1,3-oxazolidin-2-ones or nearly equal amounts of 1,3-oxazolidin-2-ones and 1,3-oxazinan-2-ones. Herein, we demonstrate that when the epoxide and N-Boc moieties are connected by a two-carbon tether, the cyclization could deliver 1,3-oxazinan-2-ones containing vicinal stereocenters, as sole regio- and diastereomers in high yields (up to 95% yield), irrespective of whether the distal epoxide substituent is alkyl or aryl, or the epoxide is cis- or trans-configured.

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Dearomative indole C3-alkylation�intramolecular iminium trapping cascade reaction of indole-C3-tethered nucleophiles is a well-known blueprint for accessing 2,3-fused indolines. In exploring this strategy, synthetic chemists have utilized diverse classes of electrophilic reagents. However, the tethered nucleophiles have mainly been limited to heteronucleophiles and enolates; exploitation of tethered arenes/heteroarenes remains unknown. We herein describe the first examples of pyrroleintercepted dearomative indole C3-allylation and benzylation of indole-tethered pyrroles toward the synthesis of 2,3-cis-fused tetracyclic indolines featuring a C3 all-carbon quaternary stereocentre. Our methodology capitalizes on the capability of NaO t Bu/ Et 3 B combination to direct the intermolecular alkylation to take place regioselectively at the indole C3 position over the other reactive sites (indole N and C2 and pyrrole C2 positions) and leverages the high nucleophilicity of the pyrrole template for the concomitant aza-Friedel−Crafts ring closure that traditionally would require an additional acid-catalyzed synthetic step. This cascade reaction is accomplished with broad substrate scope and excellent yields and chemo-, regio-, and diastereoselectivities.