Asymmetric Friedel-Crafts Alkylation of Indoles: The Control of Enantio- and Regioselectivity

Abstract

The asymmetric Friedel-Crafts reaction of indoles isa synthetic methodology that enables direct access to the enantiopure indolederivatives. In this review, work mainly carried out by You andhis co-workers on the regio- and enantioselective synthesis of indolederivatives will be discussed. Chiral Bronsted acids oriridium complexes promote highly enantioselective Friedel-Craftsreactions of indoles and 4,7-dihydroindoles starting with various electrophilicreagents, such as imines, N-tosyl-substitutedamines, β,γ-unsaturated α-keto esters,nitro-substituted olefins, aldehydes, and allyl carbonates. Thesemethodologies can be used to readily prepare diverse enantioenrichedindoles, such as indol-3-ylmethanamines, indol-2-ylmethanamines,unsymmetrical arylbis(indol-3-yl)methanes, 9-indol-3-ylfluorenes,tetrahydropyrano[3,4- B]indoles,tetrahydro-γ-carbolines, and tetrahydro-β-carbolines. 1 Introduction 2 Asymmetric Friedel-Crafts Alkylation of Indoles atthe -3-Position 2.1 Chiral Phosphoric Acids and Their Activation Mode 2.2 Asymmetric Friedel-Crafts Alkylation of Indoleswith -Imines 2.3 Asymmetric Friedel-Crafts Alkylation of Indoleswith N-Tosyl-Substituted Amines 2.4 Tandem Friedel-Crafts Alkylation of Indoles withAldehydes and Alcohols 2.5 Iridium-Catalyzed Asymmetric Friedel-Crafts Allylic Alkylationof Indoles 3 Asymmetric Friedel-Crafts Alkylation of Indoles atthe 2-Position 3.1 Asymmetric Friedel-Crafts Alkylation of 4,7-Dihydro-indoleswith Imines 3.2 Asymmetric Friedel-Crafts Alkylation of 4,7-Dihydro-indoleswith Keto Esters 3.3 Asymmetric Friedel-Crafts Alkylation of 4,7-Dihydro-indoleswith Nitro-Substituted Olefins 4 Sequential Catalysis for the Enantioselective Synthesis of PolycyclicIndoles 5 Conclusion and Outlook