Friedel–Crafts Hydroxyalkylation of Indoles with α-Keto Amides using Reusable K₃PO₄/nBu₄NBr Catalytic System in Water

Abstract

A mild and operationally simple Friedel-Crafts hydroxyalkylation of indoles with α-keto amides was developed for the first time by using catalytic amount of KPO and nBuNBr in water as solvent through a solid-liquid interface formation. The transition-metal-free protocol does not demand column chromatography purification and results in highly pure indole fused α-hydroxy amides in good to excellent yields. Reusability of the catalytic system up to five cycles and extension to a gram-scale reaction are the key advantages of this transformation. The mechanistic study involving H NMR experiments reveals that the reaction proceeds via ion exchange pathway.

Reaction of indoles with aromatic fluoromethyl ketones: an efficient synthesis of trifluoromethyl(indolyl)phenylmethanols using K2CO3/n-Bu4PBr in water

“…Next, a plausible mechanism for the preparation of multihalogen-alkylated 1-(1H-indol-3-yl)-1-phenylethan-1-ols is proposed as indicated in Scheme 3. Based on the literature [34], this reaction initiates by the formation of n-Bu 4 P + KCO 3 − salt (A) from the interaction of n-Bu4PBr and K 2 CO 3 . Intermediate A makes a hydrogen bond interaction with the NH of the 5-methoxyindole (1a) and form the adduct B.…”

Reaction of indoles with aromatic fluoromethyl ketones: An efficient synthesis of trifluoromethyl-indolyl-phenylethanols using K2CO3/nBu4PBr in water

“…Next, a plausible mechanism for the preparation of multihalogens-alkylated-1-(1H-indol-3yl)-1-phenylethan-1-ols is proposed as indicated in Scheme 3. Based on literature [17] 16 Scheme 3. Proposed mechanism for the preparation of 3a as an example.…”

Recent Advances on Direct Functionalization of Indoles in Aqueous Media

“…In 2018, Sekar et al first realized the mild and straightforward Friedel-Crafts hydroxyalkylation of indole 36 with αketo amides 37 by using K 3 PO 4 /nBu 4 NBr in water as the solvent (Scheme 10). [77] The system displayed good tolerance to aromatic and aliphatic amine-derived α-keto amides, and high-purity indole-tethered α-hydroxy amides could be ob-tained in good to excellent yields without column chromatography. It is worth noting that the recovery and reusability of the catalytic system have been proven to be up to five consecutive cycles, and the gram-level reaction has further tested the efficacy of the reaction.…”