Three Component Cascade Reaction of Cyclohexanones, Aryl Amines, and Benzoylmethylene Malonates: Cooperative Enamine-Brønsted Acid Approach to Tetrahydroindoles

Abstract

A three-component cascade reaction comprising cyclic ketones, arylamines, and benzoylmethylene malonates has been developed to access 4,5,6,7-tetrahydro-1H-indoles. The reaction was achieved through cooperative enamine-Brønsted catalysis in high yields with wide substrate scopes. Mechanistic studies identified the role of the Brønsted acid catalyst and revealed the formation of an imine intermediate, which was confirmed by X-ray crystallography.

Recent Advances in the Synthesis of Indoles with Partially Hydrogenated Benzene Ring (Tetrahydroindoles)

“…Scheme 82 Selective hydrogenation of indole using Ru and Pd catalysts Wang, Luo et al 135 developed a three-component cascade reaction comprising cyclic ketones, arylamines, and benzoylmethylene malonates to access cycloalkano con-densed pyrroles. The reaction was achieved through cooperative enamine-Brønsted catalysis in high yields with wide substrate scopes.…”

“…The reaction was achieved through cooperative enamine–Brønsted catalysis in high yields with wide substrate scopes. A proposed mechanism of the reaction involves (Scheme 81 ) 135 the formation of enamine U in situ from cyclic ketone and arylamine, which then reacts with benzoylmethylene malonate ( 242a ) through a Michael addition to give 244a . The carbonyl group is then activated by (PhO) 2 PO 2 H to initiate an intramolecular cyclization reaction V to afford W , after which the loss of water provides the final 4,5,6,7-tetrahydroindole 243a .…”

“…In addition to the methods mentioned, tetrahydroindol-4-one derivatives were obtained by a three-component reaction of phenacyl bromide, dimedone, and amines in onepot process, using sulfamic acid under ball milling conditions, 131 -cyclodextrin under neutral conditions, 132 ZnO- zeolite nanoparticle under microwave irradiations, 133 or with two step process in water/ethanol (1:1) under reflux conditions. 134 Wang, Luo et al 135 developed a three-component cascade reaction comprising cyclic ketones, arylamines, and benzoylmethylene malonates to access cycloalkano con-densed pyrroles. The reaction was achieved through cooperative enamine-Brønsted catalysis in high yields with wide substrate scopes.…”

Organocatalytic Atroposelective Construction of Pentatomic Heterobiaryl Diamines through Arylation of 5-Aminoisoxazoles with Azonaphthalenes

“…Asymmetric Michael-type reactions with various carbon nucleophiles such as indoles, 2-naphthols, , 2-naphthylamines, , as well as arylboronic acids have been reported for the construction of biaryl atropisomers. Based on these pioneering reports and our ongoing interest in the chemistry of heterocyclic scaffolds through enamine catalysis, we envisioned that the C4 position of 5-aminoisoxazole is nucleophilic and can react with azonaphthalene to deliver a privileged Friedel–Crafts aromatization product that associates diamine and isoxazole fragments into one molecule. Herein, an efficient asymmetric arylation of 5-aminoisoxazoles with azonaphthalenes via chiral phosphoric acid catalysis is reported, which provides a wide range of axially chiral heterobiaryl diamines in high yields with very good enantioselectivities (Scheme c).…”