Syntheses of N-Alkyl 2-Arylindoles from Saturated Ketones and 2-Arylethynylanilines via Cu-Catalyzed Sequential Dehydrogenation/Aza-Michael Addition/Annulation Cascade

Abstract

We describe here a Cu-catalyzed and 4-OH-TEMPO-mediated sequential dehydrogenation/aza-Michael addition/annulation cascade reaction for the construction of N-alkyl 2-arylindoles from facilely available saturated ketones and 2-arylethynylanilines. This reaction shows high regioselectivity and tolerates a variety of functional groups. Moreover, 3-alkyl-substituted indoles can also be achieved when using 2-alkylethynylanilines as starting materials.

2‐(Alkynyl)anilines and Derivatives — Versatile Reagents for Heterocyclic Synthesis

“…When triple bond was conjugated with an aromatic system (R 2 =Ar), N ‐alkylated indoles 56 were formed. Alkyl substituted o ‐alkynylanilines (R 2 =Alk) produced 3‐substituted indoles 57 [98] . Interestingly, analogous compounds could be synthesized through an oxidative palladium (II)‐catalyzed reaction between o ‐alkynylanilines and allyl alcohols [99] …”

Applications of Ethynylanilines as Substrates for Construction of Indoles and Indole‐Substituted Derivatives

“…Interestingly when the solvent and ligand was switched from ethanol to dichloroethane and jhonPhos/ Buchwald's ligand the selectivity was favoured towards formation of propelane-type indolines moiety 30 exclusively at 80°C temperature. [24] Both reactions proceed with first intramolecular 5-endo-dig hydroamination and then an 8-endo-dig cycloisomerization process. Here use of IPr ligands and the protic solvents such as ethanol has favoured the formation of the eight membered ring moiety containing indoles 31.…”

“…In the year 2020 Fei Ling et al [24] have also described copper catalyzed synthesis of N-alkyl 2-arylindoles 64 (Scheme 21) from saturated ketones 63 and 2-arylethynylanilines 64 [66] in the presense of 4-OH-TEMPO as an oxidant. [39] This strategy involves sequential steps which includes dehydrogenation, aza-Michael addition and annulation for formation of N-alkyl 2-arylindoles 64.…”

“…have described synthesis of oxocine‐fused indoles 31 through gold catalyzed intramolecular 5‐endo‐dig hydroamination followed by an 8‐endo‐dig cycloisomerization reactions of anilines with diynes 29 (Scheme 10) in ethanol solvent at 60 °C temperature. Interestingly when the solvent and ligand was switched from ethanol to dichloroethane and jhonPhos/ Buchwald's ligand the selectivity was favoured towards formation of propelane‐type indolines moiety 30 exclusively at 80 °C temperature [24] . Both reactions proceed with first intramolecular 5‐endo‐dig hydroamination and then an 8‐ endo‐dig cycloisomerization process.…”

“…In the year 2020 Fei Ling et al [24] . have also described copper catalyzed synthesis of N‐alkyl 2‐arylindoles 64 (Scheme 21) from saturated ketones 63 and 2‐arylethynylanilines 64 [66] in the presense of 4‐OH‐ TEMPO as an oxidant [39] .…”