A Journey Across Recent Advances in Catalytic and Stereoselective Alkylation of Indoles

Abstract

In this Account our recent results in relation to the catalytic and stereoselective Friedel-Crafts (FC) alkylation of indoles are described. Over the last decade, remarkable efforts have been devoted towards the replacement of the primal approaches with new more efficient, reliable, and environmentally benign strategies for the functionalization of indoles. Moreover, the emerging area of catalytic asymmetric FC processes is addressed and some examples of enantioselective alkylations of indoles via 1,4-addition to α,β-unsaturated systems and asymmetric ring-opening reaction of aromatic epoxides are described.

• 1 Introduction

• 2 Catalytic Regioselective Alkylation of Indoles

• 2.1 Michael Addition of Indoles to Enones Catalyzed by InBr₃

• 2.2 Synthesis of 1,3-Bisindolyl Ketones through 1,4-Conjugate Addition of Indoles to Indolyl Enones

• 2.3 Synthesis of 1,2,3,4-Tetrahydro-β-carbolines and Pyranyl Analogues via Intramolecular Indole Alkylation

• 2.4 InBr₃-Catalyzed Michael Addition of Indoles to Nitro­alkenes in Aqueous Media

• 2.5 Environmentally Benign Continuous and Semi-continuous Solid-Acid-Catalyzed Alkylation of Indoles

• 2.6 Regio- and Stereoselective Catalyzed Ring Opening of Enantiomerically Pure Aromatic Epoxides

• 2.7 Pd-Catalyzed Allylic Alkylation of Indoles

• 3 Catalytic and Enantioselective Alkylation of Indoles: ­Introduction.

• 3.1 BINAP-Pd(II) as a Chiral Lewis Acid for the Michael ­Addition of Indoles to α,β-Unsaturated Thioesters

• 3.2 [SalenAlCl] as the Catalyst for the Enantioselective ­Addition of Indoles to Enones

• 3.3 Asymmetric Kinetic Resolution of Racemic Internal ­Aromatic Epoxides Promoted by [SalenCrX]

• 4 Outlook

Key words

alkylations - asymmetric catalysis - electrophilic aromatic substitutions - indoles - Lewis acids

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22

Agnusdei, M.; Bandini, M.; Melloni, A.; Umani-Ronchi, A. unpublished results.

40

Mass flow rate of reactant for mass of catalyst utilized in the reactor.

44

In fact, electronic properties of aromatic epoxides are known to drive the ring-opening with indoles at the benzylic position.

47

Aliphatic epoxides were not found suitable candidates for the present catalytic indole alkylation giving the β-indolyl alcohols in poor yield as well as regioselectivity.

67

Among all the Lewis acids tested, only BINAM-Sc(OTF)₃, BINOL/AlEt₂Cl, BOX-Zn(OTf)₂, and Tol-BINAP-CuOTf led to the formation of 50 in significant yields. However the enantioselectivity recorded was poor with ee ranging from 0-36%.