Enantioselective Palladium‐Catalyzed C—H Functionalization of Indoles Using an Axially Chiral 2,2′‐Bipyridine Ligand.

Ap alladium-catalyzed enantioselective C¢ Hf unc- tionalization of indoles was achieved with an axially chiral 2,2'- bipyridine ligand, thus providing the desired indol-3-acetate derivatives with up to 98 %e e. Moreover ,t he reaction protocol was also effective for asymmetric O¢ Hi nsertion reaction of phenols using a-aryl-a-diazoacetates .T his represents the first successful application of bipyridine ligands with axial chirality in palladium-catalyzed carbene migratory insertion reactions. Functionalized indoles are ubiquitous structural motifs in am yriad of biologically active alkaloids and pharmaceuti- cals. (1) To access these privileged building blocks ,t he most straightforward approach is direct functionalization of simple and commercially available indoles .A mong the enormous efforts devoted to this area, transition-metal-catalyzed C¢H functionalization by diazo compounds stands out because of its convenience in constructing indol-3-acetate derivatives with high medicinal value. (2) Th eg roups of Fox (2c) and Hashimoto (2d) disclosed rhodium-catalyzed direct C¢ Hf unc- tionalization of indoles by carbenoids ,d erived from a-alkyl- a-diazo-acetates ,w ith excellent enantioselectivity .B ut when a-aryl-a-diazoacetates were used, neither iron (2e) nor rhodium catalysts (2f) gave satisfactory results in terms of enantioselec- tivity (Scheme 1). An interesting protocol to acquire chiral indol-3-acetate derivatives was developed by the group of Hu through enantioselective trapping of zwitterionic intermedia- tes. (2g,h) Despite the progress made recently ,d eveloping an enantioselective method for the direct functionalization of indoles using a-aryl-a-diazoacetates is still challenging and highly desirable. Palladium is an indispensable and versatile catalyst in modern organic synthesis. (3) Palladium-catalyzed carbene- transfer reactions based on migratory insertion have received considerable attention recently, (4, 5) but asymmetric versions are underexplored. Th ef ew catalytic systems developed by the groups of Hu, (6a) Feng (6b) and Zhou (6c) were successfully applied in palladium-catalyzed asymmetric carbene-transfer reactions ,b ut stagnation in the design of efficient ligands impeded development of this area. From these previous works ,w es aw an opportunity for realizing the direct palladium-catalyzed enantioselective functionalization of indoles by a-aryl-a-diazoacetates with the aid of ap roper ligand. In this context, we report ah ighly efficient palladium- catalyzed method for the enantioselective C¢ Hf unctionali- zation of indoles with an axially chiral 2,2'-bipyridine ligand. In addition, this catalytic system is also effective for asym- metric O¢H-insertion reaction of phenols. At the outset, we examined the catalytic performance of