Catalyst-free Synthesis of 6-Hydroxy Indoles via the Condensation of Carboxymethyl Cyclohexadienones and Amines

Abstract

An efficient catalyst-free synthesis of 6-hydroxy indoles from carboxymethyl cyclohexadienones and primary amines has been developed. The aza-Michael addition of the in situ formed enamine, generated through the condensation of carboxymethyl unit of the substrates with an external amine, to cyclohexadienone moiety followed by rearomatization reaction to provide such indoles. Anilines, aliphatic amines, α-chiral aliphatic amines, or even ammonia were used as amine counterpart. Some of the cyclohexadienones gave 6-amino indoles instead of 6-hydroxy indoles using the ReO catalyst. Various post methodological transformations were performed to explore the synthetic utility of the synthesized hydroxy indoles.

The Ligand Free Palladium(II)-Catalyzed Regioselective 1,2-Addition of Enol Silanes to Quinones to Access 4-Hydroxy-4-(2-oxo-2-arylethyl)cyclohexadien-1-ones and Synthetic Applications

“…The proposed mechanism (Scheme ) for the formation of indoles involves the following steps: (a) formation of diimine 12a from 3a and 2 equiv of primary amine ( 11 ); (b) tautomerization of 12a to 12b followed by aza-Michael addition of an enamine in the side chain onto the cyclohexadiene imine core to generate the intermediate 12c ; and (c) aromatization of 12c via dehydration to deliver the indole derivative 13 . Unlike the reported methodology for the related system represented by the O -methyl analogue of 3a that requires a Re 2 O 7 catalyst, this method does not require any catalyst . Thus, this method paves the way for an efficient, catalyst-free synthesis of 6-aminoindoles from carbonylmethyl cyclohexadienones and primary amines.…”

“…Unlike the reported methodology for the related system represented by the O-methyl analogue of 3a that requires a Re 2 O 7 catalyst, this method does not require any catalyst. 55 Thus, this method paves the way for an efficient, catalyst-free synthesis of 6-aminoindoles from carbonylmethyl cyclohexadienones and primary amines.…”

Gold-Catalyzed Synthesis of 6-Hydroxyindoles from Alkynylcyclohexadienones and Substituted Amines

“…Synthesis of 4-hydroxy- and 5-hydroxy-substituted indoles are easy to access by commercially available starting materials. However, syntheses of 6-hydroxyindoles are quite difficult to achieve …”

“…Our current research efforts have focused mainly on the exploration of substituted alkynes in the presence of gold catalysis . Recently, 6-hydroxyindoles were achieved by the reaction of carboxymethylcyclohexadienones with amines under metal-free reaction conditions . We were interested in aiming our focus on the reactivity of alkynyl-substituted cyclohexadienones 1 with amines 2 in the presence of a gold catalyst.…”

“…A tentative reaction mechanism can be proposed for this organic transformation (Scheme ). Initially, the gold catalyst coordinates with alkynylcyclohexadienone 1a , and it may react with aniline 2a by following a Meyer–Schuster rearrangement to give enamine intermediate IM-I , which would further generate IM-II via aza-Michael addition, followed by a rearrangement to provide 6-hydroxyindole derivative 3a .…”