Organocatalytic Enantioselective Friedel–Crafts Aminoalkylation of Indoles in the Carbocyclic Ring

Abstract

The first general catalytic method for the, so far elusive, enantioselective Friedel−Crafts functionalization of indoles in the carbocyclic ring is presented. This transformation contrasts with the usual tendency of these heterocycles to react at the azole ring. For this purpose, the four regioisomeric hydroxy carbocyclic-substituted indoles were reacted with several isatinderived ketimines, using a Cinchona alkaloid-based squaramide, in a low 0.5−5 mol % catalyst loading, as a bifunctional catalyst. This methodology allows the functionalization of indoles in every position of the carbocyclic ring in a regio-and enantioselective fashion, by switching only the position of the hydroxy group in the starting material. Furthermore, several transformations were carried out, including the reductive elimination of the hydroxy group.

Organocatalytic Enantioselective aza‐Friedel‐Crafts Reactions of Pyrazolinone Ketimines with Hydroxyindoles and Electron‐Rich Phenols

“…Notably, this method is distinct from substitution occurring at the C3‐position of hydroxyindoles . In 2016, Pedro and co‐workers reported the enantioselective aza‐Friedel‐Crafts reaction of isatin‐derived ketimines and hydroxyindoles via utilizing the activating/directing ability of hydroxyl group . Subsequently, they and Zhao further developed effective protocols for the asymmetric Friedel‐Crafts alkylation in the benzene ring of indoles employing other electrophiles.…”

Direct Asymmetric Arylation of Imines

“…Pedro and coworkers reported the first general method for the enantioselective Friedel-Crafts reaction of hydroxyindoles with isatin-derived ketimines, using a squaramide supported on the quinine skeleton as bifunctional organocatalyst (catalyst loading 0.1-5 mol %) (Scheme 56). [70] Hydroxyindoles interacted in the carbocyclic ring rather than the azole system to give the desired aminoalkylated products with high enantioselectivity. Unlike conventional Friedel-Crafts reactions, this approach enabled the introduction of substituents in every position of the carbocyclic ring of indole in a regioselective manner, by just switching the position of the activating/directing hydroxy group.…”

Organocatalyzed Asymmetric Friedel‐Crafts Reactions: An Update

“…Noticeably, hydroxyindoles 14 c and 14 d are particularly inspiring substrates, as they have two accessible ortho positions for the substitution reaction. This approach permits the regioselective aminoalkylation in only one ortho position, providing the corresponding product (Scheme 71 ) …”

“…The current model clarifies the ortho ‐regioselectivity for the nucleophiles and the R absolute configuration of the corresponding products. The effect of the catalyst/OH‐group interaction can be determined by the fact that the 5‐methoxyindole does no treat based on the optimal conditions …”