Synthesis of Indole-Fused Eight-Membered Heterocycles via Rh(III)-Catalyzed NH-Indole-Directed C–H Activation/[5+3] Annulation of 7-Phenylindoles with Methyleneoxetanones

Abstract

We report an efficient strategy for constructing indole-fused eight-membered heterocycles via a rhodium(III)-catalyzed NH-indole-directed C–H activation/[5+3] annulation of readily available 7-phenylindoles with methyleneoxetanones. This method provides direct access to benzo[4,5]azocino[3,2,1-hi]indole scaffolds, a structural motif of high relevance in natural products and bioactive molecules, yet synthetically underdeveloped. The reaction proceeds under optimized conditions using [Cp*RhCl₂]₂ (2.5 mol%) as the catalyst in methanol at 60 °C, delivering the disubstituted acrylic acid intermediates in good yields. A subsequent intramolecular amidation, mediated by TsCl/DMAP at room temperature, furnishes the eight-membered lactams in moderate to excellent yields. Salient features of this work include: (1) the use of the NH-indole group as an intrinsic directing group for chemoselective C–H activation; (2) the streamlined assembly of 1,7-fused eight-membered heterocyclic systems, expanding the toolkit for accessing medium-sized N-heterocycle; (3) broad substrate scope, tolerating diverse functional groups (e.g., CF₃, OMe, Cl, CN, CO₂Me, NPh₂, SiMe₃); (4) demonstrable synthetic utility through a gram-scale synthesis (up to 5 mmol) and a one-pot procedure without isolation of disubstituted acrylic acid intermediates; (5) Isolation and crystallographic characterization of two key rhodacyclic intermediates (a six-membered C–H/N–H cleaved species and an eight-membered alkene-insertion intermediate), confirming their role in the catalytic cycle; and (6) density functional theory (DFT) calculations that provide mechanistic insights, revealing that the transformation proceeds via a kinetically and thermodynamically favored β-oxygen elimination pathway, while the competitive β-hydride elimination is energetically disfavored.

Keywords

Rhodium / C–H activation / NH-indole-directed / Chemoselectivity / Eight-membered heterocycles / Annulation / Key intermediate / DFT calculations

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