Hypoiodite-Catalyzed Chemoselective Tandem Oxidation of Homotryptamines to Peroxy- and Epoxytetrahydropyridoindolenines

Abstract

We developed the hypoiodite-catalyzed tandem dearomative peroxycyclization of homotryptamine derivatives to peroxytetrahydropyridoindolenines under mild conditions. During the course of a mechanistic study, we found that a tandem oxidative cyclization/epoxidation as an unexpected reaction proceeded in the presence of TEMPO as an additive. Intramolecular oxidative aminocyclization of homotryptamines at the C-2 position would give tetrahydropyridoindole, a common intermediate for both reactions. Control experiments suggested that while oxidative coupling with TBHP at the C-3 position might afford peroxyindolenines, a preferential electrophilic addition of TEMPO+, which might be generated in situ by the hypoiodite-catalyzed oxidation of TEMPO, at C-3 position followed by elimination and epoxidation might give epoxyindolenines. This serendipitous finding prompted us to develop a chemoselective divergent synthesis of peroxy- and epoxyindolenines by simple modification of the reaction conditions.

I+/TBHP Catalysis For Tandem Oxidative Cyclization To Indolo[2,3‐b]quinolines

“…Based on the above observations and previous findings, [12–14] a proposed mechanism is depicted in Scheme 8. Control experiments in Scheme 6 revealed that both ionic (i. e., hypoiodite) and radical (i. e., t ‐BuO .…”

“…Based on the above observations and previous findings, [12][13][14] a proposed mechanism is depicted in Scheme 8. Control experiments in Scheme 6 revealed that both ionic (i. e., hypoiodite) and radical (i. e., t-BuO * and/or t-BuOO * ) species might be generated in situ and worked in synergy under our catalytic oxidation conditions to proceed a chemoselective tandem oxidation.…”

“…Interestingly, in sharp contrast to our previous oxidative peroxycyclization of homotryptamines in which N-substituted indoles were inert to oxidation, [12] N-Me-indole derivative 2 m could be used for this oxidative cyclization/aromatization reaction (Scheme 4). Notably, compared to 3 a-l, due to the higher solubility of the corresponding sulfonate salt 3 m, we obtained N-Me indoloquinoline 1 m as a free base in good yield after a basic work-up and column chromatography.…”

“…While the hypoiodite‐catalyzed oxidative cyclization of 2 gave dihydroindoloquinoline intermediates 4 via an ionic process, denosylative aromatization of 4 to indoloquinolines 1 might involve a free‐radical species. In the ionic process, a reversible N ‐iodination of N ‐unsubstituted indoles 2 with I + active species might afford indolyl hypoiodite 11 , which might then give 4 via intramolecular aminocyclization at the C‐2 position [12,17] . Alternatively, iodination of N ‐substituted indoles (i. e., 2 m ) at the C‐3 position might give iminium cations 12 .…”

“…Instead, a hardly soluble salt, which was determined to be quinindolin‐5‐ium nosylate 3 a by X‐ray analysis (Scheme 2d), was obtained in 76% isolated yield after simple filtration. A reaction kinetic profile analysis using in situ 1 H NMR monitoring of the reaction progress revealed the rapid consumption of 2 a to give dihydroindolo[2,3‐ b ]quinoline 4 a , an analogue of 7 , [12] as an intermediate, which was then converted to 3 a (Scheme 2c). We speculated that the enhanced acidity of benzylic protons in 4 a might lead to aromatization/denosylation to give 3 a rather than intermolecular oxidative coupling with TBHP.…”