Asymmetric Friedel-Crafts alkylation of indole with chalcones catalyzed by chiral phosphoric acids.

Arrigo Scettri,Maria Rosaria Acocella,Rosaria Villano

doi:10.3390/molecules14083030

Abstract

The reaction of indole with chalcones, to give Michael-type adducts, was found to occur with good efficiency (up to 98% yield) and moderate enantioselectivity (up to 52% e.e.) in the presence of a chiral BINOL-based phosphoric acid. Furthermore, the alkylation products can be obtained in much higher e.e.s after one only crystallization.

Highlights

The indole moiety represents the main structural feature of a variety of unnatural and natural bioactive products, such as the indole alkaloids [1,2]
With regards to chiral Bronsted Acids, good efficiency but rather poor levels of enantioselectivity were observed in the F.C. alkylation of indoles with chalcones when a camphor-based Bronsted acid was used [10], while improved enantiomeric excesses were obtained through the use of the H8-BINOL-based phosphoric acid of type 1 [11,12] (R= 4-ClC6H4) (Scheme 1, Figure 1)
Asymmetric organocatalytic F.C. alkylation of indole 3 with chalcone 4a catalyzed by 2a and 2b

Summary

Introduction

The indole moiety represents the main structural feature of a variety of unnatural and natural bioactive products, such as the indole alkaloids [1,2]. It has to be noted that different approaches have been proposed for the Michael-type Friedel-Crafts (F.C.) alkylation of indoles and they involve chiral metal-complexes catalyzed reactions [5,6,7], enantioselective organocatalytic reactions via iminium ions [8,9] and chiral Bronsted Acids [10,11]. With regards to chiral Bronsted Acids, good efficiency but rather poor levels of enantioselectivity were observed in the F.C. alkylation of indoles with chalcones when a camphor-based Bronsted acid was used [10], while improved enantiomeric excesses (up to 56% e.e.) were obtained through the use of the H8-BINOL-based phosphoric acid of type 1 [11,12] (R= 4-ClC6H4) (Scheme 1, Figure 1). The use of a variety of BINOL-derived Bronsted Acid of type (R)-2 (R= Ph2PO, Ph, 4-ClC6H4, 4-MeC6H4, 4-PhC6H4, 2-naphthyl, 3,5-(F3C)2C6H3,2,4,6-tBu3C6H2) gave good yields Taking into account that the different steric and electronic effects of the above cited substituents were found exert a deep influence, both on efficiency and enantioselectivity, we decided to investigate the catalytic properties of the BINOL-derivatives 2a (R= SiPh3), and 2b (R=4-NO2C6H4), bearing substituents with different electronic and steric properties, in the F.C. alkylation of indole with chalcones

Results and Discussion

General

Typical experimental procedure

Conclusions