Catalytic Enantioselective Friedel-Crafts Alkylation of Indoles with β,γ-Unsaturated α-Keto Phosphonates in the Presence of Chiral Palladium Complexes

Abstract

The catalytic enantioselective Friedel-Crafts alkylation reaction promoted by chiral palladium complexes is described. The treatment of indoles with b,g-unsaturated a-keto phosphonates under the mild reaction conditions afforded the corresponding Friedel-Crafts alkylation adducts with excellent enantioselectivities (up to 99% ee).The Friedel-Crafts (FC) reaction is one of the most powerful C-C bond-forming processes in organic chemistry. 1 Indole derivatives are present in many substances commonly found in nature, as well as in many compounds that show pharmacological and biological activities. Thus, the development of FC reaction of indole derivatives is important in the synthesis of natural products 2 and pharmacological and biological activities. 3 Over the past decade, tremendous effort has been devoted to the development of catalytic enantioselective FC reaction of a,b-unsaturated carbonyl compounds using chiral metal complexes 4 as well as organocatalysts. 7 Simple alkenyl esters have proven to be difficult substrates for effective chirality relay in asymmetric catalysis because of essentially low reactivity of a,b-unsaturated esters as Michael acceptors. a-Keto phosphonates, which have the ability of the phosphorus to function as a leaving group, were introduced as activated ester surrogates. Recently, several groups presented catalytic asymmetric FC reactions of indoles to b,g-unsaturated a-keto phosphonates. Evans and Yamamoto groups have developed FC reaction catalyzed by chiral Sc(OTf) 3 -pybox complexes 5 and chiral aluminium complexes. 6 Akiyama and Jørgensen groups have reported FC reaction using organocatalysts such as chiral phosphoric acid 7c and chiral H-bonding catalysts. 7b There are still some drawbacks in the previously reported procedures, such as low temperatures for high enantioselectivity, high catalyst loading, and unsatisfactory enantioselectivities. Therefore, the development of alternative catalysts for enantioselective FC reactions between indoles and b,gunsaturated a-keto phosphonates would be highly desirable. Recently, the efficient examples of the enantioselective reactions catalyzed by chiral palladium complexes were reported. 8 To the best of our knowledge, FC reaction of indoles with b,g-unsaturated a-keto phosphonates catalyzed chiral palladium complexes has not been reported.