Oxidant-controlled regioselectivity in the oxidative arylation of N-acetylindoles

Abstract

N-Acetylindoles can be oxidatively coupled with arenes such as benzene or pentafluorobenzene in dioxane. The use of Cu(OAc)(2) as the stoichiometric oxidant produces selective arylation at the 3-position of indole while AgOAc produces selective arylation at indole's 2-position.

Regioselective Oxidative Arylation of Indoles Bearing N-Alkyl Protecting Groups: Dual C−H Functionalization via a Concerted Metalation−Deprotonation Mechanism

“…The ability to couple both electron-rich and electron-poor arenes to indole substrates is incongruent with our previous work (Table 2, 25–31 ), in which acidic conditions could not couple heteroaromatic substrates with pentafluorobenzene,13 and basic conditions could not couple N -acetylindoles with anisole 15. To explain these phenomena, we hypothesized that the optimized, buffered reaction conditions allowed for mechanistic promiscuity, whereby the simple arene, like the indole substrate, could be palladated by either electrophilic substitution or proton abstraction processes.…”

“…Additionally, both groups found that the selectivity for arylation at either the 2- or 3-position of the indole was influenced by the choice of oxidant: AgOAc favoring the 2-aryl product, and Cu(OAc) 2 favoring arylation at the 3-position 15,16. However, none of these conditions were compatible with N -alkylindoles, providing negligible yields and a loss of regiochemical control, regardless of the oxidant.…”

Transition‐Metal‐Catalyzed Direct Arylation of (Hetero)Arenes by CH Bond Cleavage

“…[67] Palladium-catalyzed oxidative arylation of benzofurans was independently reported by DeBoef and co-workers, who devised reaction conditions for the use of molecular oxygen as the terminal oxidant. [68] Here, high regioselectivities were ensured by the use of heteropolymolybdovanadic acid as an additive (Scheme 35).…”

Palladium-catalyzed dual C–H or N–H functionalization of unfunctionalized indole derivatives with alkenes and arenes

“…In addition to the effect of Cu(OAc) 2 and AgOAc as oxidant, a determinant role on the selectivity of direct C–H to C–H cross-coupling reactions was played by the acidity of the medium, as shown by reactions carried out in the presence of AcOH [58–59]. Based on experimental and computational data, a concerted metalation–deprotonation of the arene was hypothesized to explain the mechanism for C–H palladation.…”