Piao Lu, Siqi Zhang, Xiao Tan, Shao‐Fei Ni, Qiufeng Huang
Comprehensive Summary 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*RhCl 2 ] 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 ., CF 3 , OMe, Cl, CN, CO 2 Me, NPh 2 , SiMe 3 ); (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.