Enantioselective N-Alkylation of Indoles via an Intermolecular Aza-Wacker-Type Reaction

Abstract

The development of an intermolecular and enantioselective aza-Wacker reaction is described. Using indoles as the N-source, a selection of alkenols as the coupling partner enables selective β-hydride elimination towards the alcohol. This strategy preserves the newly formed stereocenter by preventing the formation of traditionally observed enamine products. Allylic and homoallylic alcohols with a variety of functional groups are compatible with the reaction in high enantioselectivity. Isotopic-labeling experiments support a syn amino-palladation mechanism for this new class of aza-Wacker reactions.

Iridium‐Catalyzed Enantioselective Intermolecular Indole C2‐Allylation

“…Awide variety of substituents were well tolerated at the C3-position of indole including alkyl, aryl, benzyl and allyl as well as halide functionality [21] at the C3-, C5-and C6-positions of indole,a ll providing their corresponding C2-allylated products in excellent yields and enantioselectivities.T he lower yield obtained for 3-phenyl-substituted allylated product 3p was due to the competitive formation of propiophenone side-product 4;the extent of side-product formation was reduced as steric bulk decreased at the C3-position (phenyl ! benzyl !…”

Iridium‐Catalyzed Enantioselective Intermolecular Indole C2‐Allylation

“…A wide variety of substituents were well tolerated at the C3‐position of indole including alkyl, aryl, benzyl and allyl as well as halide functionality at the C3‐, C5‐ and C6‐positions of indole, all providing their corresponding C2‐allylated products in excellent yields and enantioselectivities. The lower yield obtained for 3‐phenyl‐substituted allylated product 3 p was due to the competitive formation of propiophenone side‐product 4 ; the extent of side‐product formation was reduced as steric bulk decreased at the C3‐position (phenyl → benzyl → allyl) and could also be suppressed by using increased indole equivalents (see earlier optimization).…”

Synthesis of Allylamine Derivatives via Intermolecular Aza‐Wacker‐Type Reaction Promoted by Palladium‐SPRIX Catalyst

“…Although the aza-Wacker-type cyclization has been widely investigated, [14,15] the successful intermolecular reaction is scarce. In the reported intermolecular reactions, the substrate is highly limited to a terminal olefin [16,17] or alkenols, [18] which transformed to an enamine or amino-aldehyde, respectively. Although a few examples of internal alkenes have been reported, they are limited to cyclic systems.…”